JP2018517693A - Heterocyclic alkyl derivative compounds as selective histone deacetylase inhibitors and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention relates to novel heterocyclic alkyl derivatives having histone deacetylase (HDAC) inhibitory activity, optical isomers thereof, or pharmaceutically acceptable salts thereof, and their use for producing a drug. The present invention relates to a pharmaceutical composition containing these, a treatment method using the composition, and a method for producing the same. Heterocyclic alkyl derivatives as novel selective histone deacetylase (HDAC) inhibitors according to the present invention include cell proliferative diseases, inflammatory diseases, autosomal dominant genetic diseases, metabolic diseases caused by genetic factors, It is effective in the treatment of histone deacetylase-mediated diseases such as autoimmune diseases, acute chronic neurological diseases, hypertrophy, heart failure, eye diseases, or neurodegenerative diseases.
[Selection figure] None

Description

  The present invention relates to a novel heterocyclic alkyl derivative, more specifically, a novel heterocyclic alkyl derivative having a histone deacetylase (HDAC) inhibitory activity, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The present invention relates to salts, their use in the manufacture of medicaments for the treatment of HDAC-mediated diseases, pharmaceutical compositions containing them and methods of treatment using said compositions, and methods of their production.

  Transcriptional regulation of cells is a complex biological process. One of its basic principles is the regulation by post-translational modification of histone proteins H2A / B, H3, and H4 that form an octamer histone core complex. These complex N-terminal modifications by acetylation or methylation of lysine residues and phosphorylation of serine residues form part of the so-called “histone code” (Strahl & Ellis, Nature 403, 41-45, 2000).

  In a simple model, acetylation of a positively charged lysine residue reduces the affinity for negatively charged DNA and facilitates entry of transcription factors.

Histone acetylation and deacetylation are catalyzed by histone acetyltransferase (HAT) and histone deacetylase (HDAC), respectively. HDACs are associated with transcription repressor complexes and convert chromatin to a transcriptionally inactive silent structure (Marks et al., Nature cancer Rev. 1, 189-202, 2001). The converse is true for HAT associated with the transcriptional activator complex. To date, three different classes of HDACs, namely class I (HDAC1-3, 8; Mr = 42-55 kDa), which are mainly in the nucleus and are sensitive to inhibition by trichostatin A (TSA), Class II (HDAC4-7, 9, 10; Mr = 120-130 kDa) that are TSA sensitive, and class III SIRT1-7 that are distinguished by NAD ⁺ dependence and TSA insensitivity are known.

  Histone deacetylase (HDAC) inhibitors constitute a new class of anticancer agents with differentiation and potosis inducing activity. Targeting histone deacetylase (HDAC) affects histone (protein) acetylation and chromatin structure, leading to complex transcriptional reprogramming, eg, reactivation of tumor suppressor genes and repression of oncogenes To do. In addition to causing acetylation of the N-terminal lysine residue in the core histone protein, there are non-histone targets important for cancer cell biology such as heat shock protein (HSP90), tubulin or p53 tumor suppressor protein. Therefore, HDAC inhibitors have shown utility in animal models for inflammatory diseases, rheumatoid arthritis, and neurodegenerative diseases, so that they can treat metabolic diseases due to genetic factors as well as anti-cancers. It can also be used for treatment of autoimmune diseases.

  Thus, examples of histone deacetylase-mediated diseases related to HDAC inhibition include cell proliferative diseases such as cancer that is a malignant tumor disease; Crohn's disease, ulcerative colitis, or inflammatory bowel disease Inflammatory diseases such as; autosomal dominant genetic diseases such as Huntington's disease, Down syndrome, Edwards syndrome, or Patou syndrome; diabetes, Neiman-Pick disease, Gaucher disease, phenylketonuria, Wilson's disease, cystic fibrosis, liver Metabolic disease due to genetic factors such as fibrosis, renal fibrosis, pulmonary fibrosis, or fibrosis such as cutaneous fibroma; asthma, rheumatoid disease, lupus erythematosus, psoriasis, psoriatic arthritis, multiple sclerosis, Behcet's disease, or Autoimmune diseases such as rejection after organ transplantation; acute chronic gods such as stroke or polycystic kidney disease Diseases; hypertrophy such as cardiac hypertrophy; heart failure such as congestive heart failure or hemorrhagic heart failure; eye diseases such as glaucoma, dry eye, dry macular degeneration, wet macular degeneration, diabetic retinopathy, or uveitis; Examples include neurodegenerative diseases such as amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, spinal muscular atrophy, or Alzheimer's disease, and other symptoms and diseases resulting from abnormal function of the HDAC enzyme.

  The HDAC inhibitors that have been clarified so far depend on their structures: 1) short chain fatty acid (butyric acid, valproic acid), 2) hydroxamic acid (trichostatin A, SAHA, LBH) -589), 3) cyclic peptides (desepteptide) 4) benzamide (MS-275, MGCD-0103) (Sonia et al., International Journal of oncology 37, 6) 646, 2008). Many of these histone deacetylase inhibitors (such as SAHA, LBH-589, and MS-275) are effective not only in animal models, but also in inhibiting growth, differentiation, and apoptosis of various transformed cells in the medium. (Marks, PA et al. Curr Opin. Oncol. 2001. 1.477-477) and HDAC inhibitors such as SAHA, LBH-589, and MS-275 treat various cancer diseases. Have been evaluated in clinical studies for this purpose (Johnston. RW Nat. Rev. Drug Discov. 2002. 287-299). Currently, representative compounds of HDAC inhibitors include hydroxamic acid compounds, SAHA (US Reissued Patent Publication RE38506), Zolinza, Vorinostat, PXD101 (International Patent Publication WO02 / 30879, Belinostat), LBH-589 ( There are International Patent Publication Nos. WO02 / 22577, Panobinostat), MS-275 (European Patent Publication No. 0847992) and MGCD0103 (International Publication No. WO04 / 69823) which are benzamide compounds. SAHA was approved in October 2006 and is used as a therapeutic agent for CTCL (cutaneous T-cell lymphoma). Although it has further expanded the indication, it has disadvantages in terms of efficacy and side effects. It is known (Cancer Res 2006, 66, 5781-5789).

  As described above, various HDAC inhibitors are in the preclinical or clinical development stage, but until now, only non-selective HDAC inhibitors are known as anticancer agents. In the case of non-selective HDACs inhibitors, it is generally known that high doses cause side effects such as fatigue and nausea (Piekarz et al., Pharmaceuticals, 2010, 3, 2751). -2767). These side effects are reported to be caused by suppression of class I HDACs, and due to these side effects, non-selective HDACs inhibitors have been restricted in drug development in fields other than anticancer agents. (Witt et al., Cancer Letters, 2009, 277, 8-21).

  On the other hand, in the case of selective class II HDAC inhibition, there is a report that the toxicity seen in class I HDAC inhibition does not appear, and if selective HDAC inhibitors are developed, side effects such as toxicity due to non-selective HDAC inhibition can be solved. And selective HDAC inhibitors may be developed as effective therapeutic agents for various diseases (Mattias et al., Mol. Cell. Biol., 2008, 28, 1688-1701).

  In particular, HDAC6, one of the Class IIb HDACs, is mainly present in the cytoplasm and is involved in the deacetylation of a number of non-histone substrates (HSP90, cortactin, etc.) including tubulin proteins. (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains, and the C-terminal zinc finger domain can bind to a ubiquitinated protein. Since HDAC6 has a number of non-histone proteins as substrates, it is a cancer, inflammatory disease, autoimmune disease, neurological disease, and neurodegenerative disease ( neurodegenerative disorders) are known to play important roles in various diseases (Santo et al., Blood 2012 119: 2579-258; Vishwakarma et al., International Immunopharmacology 72, H et al., J. Neurol. Sci. 2011, 304, 1-8).

  Thus, non-selective inhibition for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative diseases, etc. There is a need to develop selective HDAC6 inhibitors that have no side effects unlike drugs.

International Patent Publication No. WO2011 / 091213 (20111.7.28 published): ACY-1215

  An object of the present invention is to provide a novel compound having selective HDAC inhibitory activity, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

  Another object of the present invention is to provide a pharmaceutical composition containing a novel compound having high selective HDAC inhibitory activity, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

  Another object of the present invention is to provide these production methods.

  Another object of the present invention is to provide a pharmacological agent comprising said compound for the treatment of diseases associated with HDAC activity, including cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative diseases and the like. It is to provide a composition.

  Another object of the present invention is to provide these uses in the manufacture of a medicament for the treatment of HDAC-mediated diseases such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases, or neurodegenerative diseases. is there.

  Another object of the present invention is cancer, inflammatory disease, autoimmune disease, neurological disease, or neurodegenerative disease comprising administration of a therapeutically effective amount of a pharmaceutical composition containing said compound. It is to provide a method for treating HDAC-mediated diseases such as

  The present inventors have discovered a novel compound having an HDAC inhibitory activity and used it for the suppression or treatment of histone deacetylase-mediated diseases, thereby completing the present invention.

Novel HDAC inhibitor In order to solve the above-mentioned object, the present invention provides a compound of the following formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In Formula I, X is

A heterocyclic alkyl selected from the group consisting of:
(Where Z and W are each independently C or N, and at least one of Z and W is N;
a, b, c, and d are each independently 1, 2, or 3,
R ₃ , R ₄ , R ₅ , and R ₆ are each independently —H or —C ₁ -C ₄ alkyl)
Y is C or N;
A and B are each independently, -C ₁ -C ₄ alkyl, -C ₆ -C ₁₀ aryl, -C ₃ -C ₁₂ heteroaryl, -C ₃ -C ₁₀ cycloalkyl, -C ₂ -C ₁₀ Heterocycloalkyl, or —C ₃ -C ₁₀ cycloalkenyl, wherein one or more hydrogens of —C ₁ -C ₄ alkyl may be substituted with —OH or halogen, —C ₆ — or C ₁₀ aryl, -C ₃ -C ₁₂ heteroaryl, -C ₃ -C ₁₀ cycloalkyl, -C ₂ -C ₁₀ heterocycloalkyl, and -C ₃ -C ₁₀ cycloalkenyl is unsubstituted respectively, Or one or more hydrogens may be optionally substituted with —OH, —C ₁ -C ₄ alkyl, —OC ₁ -C ₄ alkyl, —CF ₃ , or halogen);
Q is C═O or SO ₂ ;
R ₁ is —H or —C ₁ -C ₄ alkyl;
R ₂ is —H, —OH, —C ₁ -C ₄ alkyl, —C ₁ -C ₄ alkyl hydroxy, halogen, or nothing (wherein when Y is C, R ₂ is — H, —OH, —C ₁ -C ₄ alkyl, or —C ₁ -C ₄ alkyl hydroxy, and when Y is N, R ₂ is null); 3, or 4.

According to one embodiment of the present invention, X is
Is;

(Where Z and W are each independently C or N, and at least one of Z and W is N;
a, b, c, and d are each independently 1, 2, or 3;
R ₃ , R ₄ , R ₅ , and R ₆ are each independently —H or —C ₁ -C ₄ alkyl)
Y is C or N;
A and B are each independently —C ₁ -C ₄ alkyl, —C ₆ -C ₁₀ aryl, or —C ₃ -C ₁₂ heteroaryl (wherein one of —C ₁ -C ₄ alkyl). One or more hydrogens may be substituted with —OH or halogen, and —C ₆ -C ₁₀ aryl or —C ₃ -C ₁₂ heteroaryl are each unsubstituted or substituted with one or more hydrogens. Optionally substituted with —OH, —C ₁ -C ₄ alkyl, —OC ₁ -C ₄ alkyl, —CF ₃ , or halogen);
Q is C═O or SO ₂ ;
R ₁ is —H or —C ₁ -C ₄ alkyl;
R ₂ is —H, —OH, halogen, or null (where Y is C, R ₂ is —H, —OH, or halogen, and Y is N) , R ₂ is null); and n may be 1, 2, 3, or 4.

According to another embodiment of the present invention, X is
Is;

(Where Z and W are each independently C or N, and at least one of Z and W is N;
R ₃ and R ₄ are each independently —H or —C ₁ -C ₄ alkyl)
Y is C or N;
A and B are each independently —C ₁ -C ₄ alkyl, —C ₆ -C ₁₀ aryl, or —C ₃ -C ₁₂ heteroaryl (wherein one of —C ₁ -C ₄ alkyl). One or more hydrogens may be substituted with —OH or halogen, and —C ₆ -C ₁₀ aryl or —C ₃ -C ₁₂ heteroaryl are each unsubstituted or substituted with one or more hydrogens. Optionally substituted with —OH, —C ₁ -C ₄ alkyl, —OC ₁ -C ₄ alkyl, —CF ₃ , or halogen);
Q is C = O;
R ₁ is —H or —C ₁ -C ₄ alkyl;
R ₂ is —H, —OH, halogen, or null (where Y is C, R ₂ is —H, —OH, or halogen, and Y is N) , R ₂ is null); and n may be 3.

The compounds represented by Formula I of the present invention are as shown in Tables 1 to 3 below:

  In the present invention, the compounds described in Tables 1 to 3 or pharmaceutically acceptable salts thereof are selected from the group consisting of compounds 1102, 1124, 1188, 1189, 1190, 1209, 1221, 1224, 1241, and 1243. Those selected are preferred, more preferably those selected from the group consisting of compounds 1102, 1124, 1188, and 1209.

  In the present invention, the pharmaceutically acceptable salt means a salt usually used in the pharmaceutical industry, for example, inorganic ion salts, hydrochloric acid, nitric acid, phosphoric acid produced with calcium, potassium, sodium, magnesium and the like. , Inorganic acid salts, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid , Organic acid salt made from propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, hydroiodic acid, methanesulfone Manufactured with acids, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc. There are amino acid salts produced with sulfonates, glycine, arginine, lysine, etc., and amine salts produced with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but these listed salts mean by the present invention The type of salt to be used is not limited.

  The compound of Formula I may contain one or more asymmetric carbons, thereby allowing racemates, racemic mixtures, single enantiomers, mixtures of partial stereoisomers, and respective partial stereoisomers. May be present. These isomers can be separated by conventional techniques, for example, the compound of formula I by resolution such as column chromatography or HPLC. Alternatively, each stereoisomer of a compound of formula I may be synthesized stereospecifically using optically pure starting materials and / or reagents of known sequence.

Composition containing novel HDAC inhibitor compound, use thereof and method of treatment using the same The present invention effectively uses a compound represented by the following chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: Provided is a pharmaceutical composition for preventing or treating a histone deacetylase-mediated disease contained as a component.

R ₁ , R ₂ , A, B, X, Y, Q, and n are as defined above.

  Examples of histone deacetylase-mediated diseases include cell proliferative diseases such as cancer that is a malignant tumor disease; inflammatory diseases such as Crohn's disease, ulcerative colitis, or inflammatory bowel disease; Huntington's disease, Down's syndrome, Edwards Autosomal dominant genetic disorders such as Syndrome or Patou Syndrome; diabetes, Niemann-Pick disease, Gaucher disease, phenylketonuria, Wilson disease, cystic fibrosis, liver fibrosis, renal fibrosis, pulmonary fibrosis, or skin Metabolic diseases due to genetic factors such as fibrosis such as fibrosis; autoimmune diseases such as asthma, rheumatoid disease, lupus erythematosus, psoriasis, psoriatic arthritis, multiple sclerosis, Behcet's disease, or rejection after organ transplantation; stroke Or acute chronic neurological disease such as polycystic kidney disease; hypertrophy such as cardiac hypertrophy; heart failure such as congestive heart failure or hemorrhagic heart failure; green Disorders, dry eye, dry macular degeneration, wet macular degeneration, diabetic retinopathy, or uveitis; amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, spinal muscular atrophy, Alternatively, neurodegenerative diseases such as Alzheimer's disease are included, and other symptoms and diseases caused by the abnormal function of the HDAC enzyme are also included.

  The pharmaceutically acceptable salt is as described in the pharmaceutically acceptable salt of the compound represented by Formula I of the present invention.

  The pharmaceutical composition of the present invention comprises, for administration, a pharmaceutically acceptable carrier in addition to the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 1 or more types may be further included. The pharmaceutically acceptable carrier is physiological saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of two or more of these components. Other usual additives such as an antioxidant, a buffer solution, a bacteriostatic agent and the like may be added as necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants can be further added to prepare injectable dosage forms such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, or tablets. May be used. Accordingly, the composition of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository and the like. These preparations may be prepared according to the usual methods used for formulation in the industry or the methods disclosed in Remington's Pharmaceutical Sciences (recent edition), Mack Publishing Company, Easton PA, depending on the respective disease and / or ingredient. May be formulated.

  The compositions of the present invention may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally, or topically), depending on the desired method, The range varies depending on body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, disease severity, and the like. The daily dose of the derivative compound of the formula I of the present invention is about 1 to 500 mg / kg, preferably 5 to 100 mg / kg, and can be administered once to several times a day. Good.

  The pharmaceutical composition of the present invention further comprises one or more active ingredients having the same or similar medicinal effect in addition to the compound represented by the above chemical formula I, optical isomers thereof, or pharmaceutically acceptable salts thereof. May be included.

  The present invention provides a method for preventing or treating a histone deacetylase-mediated disease comprising administration of a therapeutically effective amount of a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Provide a way to do it.

  The term “therapeutically effective amount” used in the present invention means the amount of the compound represented by Formula I effective for the prevention or treatment of histone deacetylase-mediated diseases.

  In addition, the present invention provides a histone deacetylase (HDAC) comprising administering an effective amount of the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a mammal including a human. Provide a method of inhibiting

  The method for preventing or treating a histone deacetylase-mediated disease of the present invention not only treats the disease itself but also inhibits or avoids the symptoms by administering the compound represented by Formula I. To include. In disease management, the prophylactic or therapeutic capacity of a particular active ingredient varies depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Volume and frequency will vary depending on the age, weight and response of the individual patient. Appropriate doses and dosages can be readily selected by those with ordinary knowledge in the art who are willing to consider these factors. The method for preventing or treating a histone deacetylase-mediated disease of the present invention further comprises administering a therapeutically effective amount of an active preparation useful for treatment of the disease together with the compound represented by Formula I. In addition to the compound of formula I, a synergistic or additive effect can be obtained by using additional active formulations.

  Furthermore, the present invention seeks to provide the use of the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of HDAC-mediated diseases. The compound represented by Formula I for the manufacture of a drug may be mixed with pharmaceutically acceptable adjuvants, diluents, carriers and the like, and is manufactured as a combined preparation together with other active preparations. Therefore, it can have a synergistic effect.

  The matters described in the use, composition and treatment method of the present invention apply in the same manner as long as they do not contradict each other.

Method for Producing Novel HDAC Inhibiting Compound The present invention provides a method for producing a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. These production methods will be described by the following reaction formulas 1 to 10.

  As illustrated in the above [Reaction Scheme 1], the chemical formula 1-1 is converted into methyl 6-aminohexanoate hydrochloride, methyl 7-aminoheptanoate hydrochloride, or methyl 8-aminooctanonoate hydrochloride. (Chemical Formula 1-2) and a urea reaction are performed to synthesize Chemical Formula 1-3, and then potassium hydroxide (KOH), methanol, and a hydroxylamine aqueous solution are added and reacted at room temperature, whereby final compounds 1102, 1240, and 1257 is synthesized.

  Also, after synthesizing chemical formula 1-4 by reacting chemical formula 1-3 introduced with methyl 7-aminoheptanoate with iodomethane, potassium hydroxide (KOH), methanol, hydroxylamine aqueous solution was added, and at room temperature. The final compound 1213 is synthesized by reacting.

  As shown in [Reaction Formula 2], Chemical Formula 2-1 is subjected to a urea reaction with methyl 7-aminoheptanoate hydrochloride (Chemical Formula 1-2) to synthesize Chemical Formula 2-2, and then 4M Reaction with hydrochloric acid solution synthesizes chemical formula 2-5 from which the amino protecting group (Boc) has been removed. After chemical formula 2-3 is reacted with thionyl chloride to synthesize chemical formula 2-4, a substitution reaction is performed with chemical formula 2-5 to synthesize chemical formula 2-6. Final compounds 1223, 1224, 1647, and 1648 are synthesized by adding potassium hydroxide (KOH), methanol, and an aqueous hydroxylamine solution and reacting at room temperature.

  As shown in [Reaction Formula 3], Chemical Formula 3-1 is reduced with sodium borohydride to synthesize Chemical Formula 3-2 and then reacted with methanesulfonyl chloride to synthesize Chemical Formula 3-3. To do. After performing substitution reaction with Chemical Formula 2-5 to synthesize Chemical Formula 3-4, potassium hydroxide (KOH), methanol, hydroxylamine aqueous solution is added and reacted at room temperature to synthesize Final Compound 1222.

  As shown in the above [Reaction Scheme 4], the chemical formula 4-1 is substituted with (2S, 6R) -2,6-dimethylpiperazine (formula 4-2) to synthesize the chemical formula 4-3. The urea is reacted with methyl 7-aminoheptanoate hydrochloride to synthesize Chemical Formula 4-4. The final compound 1188 is synthesized by adding potassium hydroxide (KOH), methanol, and an aqueous hydroxylamine solution and reacting at room temperature.

  Further, after reacting the chemical formula 4-1 with the A-Boc compound, the protecting group (Boc) is removed with a 4M hydrochloric acid solution to synthesize the chemical formula 4-6. After performing urea reaction with chemical formula 1-2 to synthesize chemical formula 4-7, potassium hydroxide (KOH), methanol, hydroxylamine aqueous solution is added and reacted at room temperature, whereby the final compounds 1189, 1190, 1763, and 1764 are reacted. Is synthesized.

  As shown in the above [Reaction Formula 5], the chemical formula 5-1 is substituted with (chloromethylene) dibenzene (chemical formula 4-1) to synthesize the chemical formula 5-2, and then lithium hydroxide (LiOH). A hydrolysis reaction is carried out to synthesize Chemical Formula 5-3. After synthesizing Formula 5-4 by amide bond reaction with methyl 6-aminohexanoate hydrochloride, methyl 7-aminoheptanoate hydrochloride, or methyl 8-aminooctanoate hydrochloride, potassium hydroxide (KOH) The final compounds 1209, 1316, and 1317 are synthesized by adding an aqueous solution of methanol and hydroxylamine and reacting at room temperature.

  Further, after chemical formula 5-4 having methyl 7-aminoheptanoate introduced is reacted with iodomethane to synthesize chemical formula 5-5, potassium hydroxide (KOH), methanol, and an aqueous hydroxylamine solution are added, and at room temperature. The final compound 1256 is synthesized by reacting.

  As illustrated in [Reaction Formula 6], Chemical Formula 6-2 is synthesized by reductive amination reaction between Chemical Formula 6-1 and aniline, and then Buckwald reaction is performed to synthesize Chemical Formula 6-3. Chemical formula 6-3 is reacted with 4M hydrochloric acid solution to remove the amino protecting group (Boc) and then reacted with saturated sodium hydrogen carbonate solution to synthesize chemical formula 6-5. After synthesizing Chemical Formula 6-6 by reacting with methyl 7-aminoheptanoate hydrochloride (Chemical Formula 1-2), potassium hydroxide (KOH), methanol, hydroxylamine aqueous solution is added and reacted at room temperature. Final compounds 1221, 1719, 1726, and 1734 are synthesized.

  As shown in the above [Reaction Scheme 7], after reacting Chemical Formula 7-1 with 4-nitrophenyl carbonochloridate (Chemical Formula 7-2) to synthesize Chemical Formula 7-3, methyl 7-amino is synthesized. Substitution reaction with heptanoate hydrochloride (Chemical Formula 1-2) is performed to synthesize Chemical Formula 7-4. The final compound 1124 is synthesized by adding potassium hydroxide (KOH), methanol, and an aqueous hydroxylamine solution and reacting at room temperature.

  Chemical Formula 7-1 is synthesized by reacting with methyl 7-aminoheptanoate hydrochloride (Chemical Formula 1-2) by urea reaction to synthesize Chemical Formula 7-4 and then reacting with diethylaminosulfur trifluoride (DAST). Synthesize 7-5. The final compound 1649 is synthesized by adding potassium hydroxide (KOH), methanol, and an aqueous hydroxylamine solution and reacting at room temperature.

  As illustrated in [Reaction Formula 8], Chemical Formula 8-1 is reacted with methyl trifluoromethanesulfonate (Chemical Formula 8-2) to synthesize Chemical Formula 8-3. After reacting with diphenyl (piperidin-4-yl) methanol (Chemical Formula 7-1) to synthesize Chemical Formula 8-4, it is reacted with methyl trifluoromethanesulfonate (Chemical Formula 8-2) to synthesize Chemical Formula 8-5. After reacting with methyl 7-aminoheptanoate hydrochloride (Chemical Formula 1-2) to synthesize Chemical Formula 8-6, potassium hydroxide (KOH), methanol, aqueous hydroxylamine solution was added and reacted at room temperature, The final compound 1210 is synthesized.

  As shown in [Reaction Scheme 9], a reductive amination reaction between Chemical Formula 2-5 and acetophenone was performed to synthesize Chemical Formula 9-2, and then potassium hydroxide (KOH), methanol The final compound 1241 is synthesized by adding an aqueous hydroxylamine solution and reacting at room temperature.

  As shown in [Reaction Formula 10], a reductive amination reaction between Chemical Formula 10-1 and acetophenone is performed to synthesize Chemical Formula 10-2, and then hydrolyzed with lithium hydroxide (LiOH). A decomposition reaction is performed to synthesize Chemical Formula 10-3. After synthesizing Chemical Formula 10-4 by amide bond reaction with methyl 7-aminoheptanoate hydrochloride, potassium hydroxide (KOH), methanol, and aqueous hydroxylamine solution are added and reacted at room temperature to give the final compound 1243. Synthesize.

  The compound represented by Formula I of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can selectively inhibit HDAC, and is capable of inhibiting histone deacetylase-mediated diseases. It is remarkably excellent in prevention or treatment.

FIG. 1 shows the results of confirming the arthritis ameliorating effect by administration of Compound 1102 in an adjuvant-induced arthritis model.

  Hereinafter, preferred examples will be presented to help understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by these examples.

Unless otherwise stated, the reagents and solvents described below were purchased from Sigma-Aldrich, TCI, HPLC was Waters e2695, and silica gel for column chromatography was Merck (230-400 mesh). . ¹ H-NMR data was measured using Bruker 400 MHz, and Agilent 1100 series was used as Mass Spectrum.

Example 1: Synthesis of compound 1102 Step 1: Synthesis of methyl 7- (4-benzhydrylpiperazine-1-carboxamide) heptanoate (Formula 1-3)

1-benzhydrylpiperazine (0.200 g, 0.793 mmol), methyl 7-aminoheptanoate (0.151 g, 0.951 mmol), triphosgene (0.118 g, 0.396 mmol), and DIPEA (0.415 mL) A solution of 2.378 mmol) in methylene chloride (5 mL) at room temperature was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride, and then filtered through a plastic filter to remove the solid residue and the aqueous solution layer, followed by concentration under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ ; 1% aqueous formic acid (methanoic acid) / acetonitrile = 100% -20%), passed through an SPE cartridge (PL-HCO ₃ resin), concentrated, The desired chemical formula 1-3 (0.075 g, 21.6%) was obtained as a pale yellow oil.

Step 2: Synthesis of 4-benzhydryl-N- (7- (hydroxyamino) -7-oxoheptyl) piperazine-1-carboxamide (Compound 1102)

  Formula 1-3 (0.075 g, 0.171 mmol), hydroxylamine (50.00% aqueous solution, 0.210 mL, 3.428 mmol), and potassium hydroxide (0.096 g, 1.714 mmol) prepared in Step 1 ) In methanol (3 mL) at room temperature was stirred at the same temperature for 30 minutes. After the solvent was removed from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the concentrate and stirred, and the precipitated solid was filtered, washed with water, dried, and the desired compound 1102 ( 0.047 g, 62.5%) was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (brs, 1H), 7.42 (d, 4H, J = 7.2 Hz), 7.29 (t, 4H, J = 7.5 Hz), 7.18 (t, 2H, J = 7.3 Hz), 6.40 (t, 1H, J = 5.3 Hz), 4.28 (s, 1H), 3.27 (s, 4H), 2.98-2.93 (m, 2H), 2.08 (s, 4H), 1.89 ( t, 2H, J = 7.3 Hz), 1.44-1.43 (m, 2H), 1.34-1.33 (m, 2H), 1.20 (s, 4H); MS (ESI) m / z 439.6 (M ⁺ + H).

Example 2: Synthesis of compound 1124 Step 1: Synthesis of 4-nitrophenyl 4- (hydroxydiphenylmethyl) piperidine-1-carboxylate (Formula 7-3)

To a solution of diphenyl (piperidin-4-yl) methanol (0.100 g, 0.374 mmol) and triethylamine (0.104 mL, 0.748 mmol) in methylene chloride (5 mL) at 0 ° C., 4-nitrophenyl chloroformate ( 0.083 g, 0.411 mmol) was added and stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridge ethyl acetate / hexane = 0% to 20%), the desired Formula 7-3 (0.152 g, 94.0%) as a colorless oil Got as.

Step 2: Synthesis of methyl 7- (4- (hydroxydiphenylmethyl) piperidine-1-carboxamide) heptanoate (Formula 7-4)

Formula 7-3 (0.152 g, 0.351 mmol), methyl 7-aminoheptanoate hydrochloride (0.280 g, 1.757 mmol), and potassium carbonate (0.097 g, 0.703 mmol) prepared in Step 1. ) In N, N-dimethylformamide (5 mL) at room temperature was stirred at 100 ° C. for 17 hours, and then the temperature was lowered to room temperature to complete the reaction. After the solvent was removed from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 10% to 40%) to obtain the desired chemical formula 7-4 ( 0.075 g, 39.4%) was obtained as an orange oil.

Step 3: Synthesis of N- (7- (hydroxyamino) -7-oxoheptyl) -4- (hydroxydiphenylmethyl) piperidine-1-carboxamide (Compound 1124)

  Formula 7-4 (0.075 g, 0.166 mmol), hydroxylamine (50.00% aqueous solution, 0.203 mL, 3.314 mmol), and potassium hydroxide (0.093 g, 1.657 mmol) prepared in Step 2 ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The precipitated solid was filtered, washed with hexane and dried to give the desired compound 1124 (0.007 g, 9.3%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (brs, 1H), 7.52 (d, 4H, J = 7.6 Hz), 7.27 (t, 4H, J = 7.7 Hz), 7.13 (t, 2H, J = 7.3 Hz), 6.30 (t, 1H, J = 5.3 Hz), 5.32 (brs, 1H), 3.94 (d, 2H, J = 13.4 Hz), 2.99-2.94 (m, 2H), 2.67-2.58 ( m, 3H), 1.91 (t, 2 H, J = 7.4 Hz), 1.48-1.46 (m, 2H), 1.35-1.34 (m, 2H), 1.30-1.25 (m, 6H).

Example 3: Synthesis of compound 1188 Step 1: Synthesis of (3S, 5R) -1-benzhydryl-3,5-dimethylpiperazine (Formula 4-3)

(2R, 6S) -2,6-dimethylpiperazine (1.000 g, 8.757 mmol), (chloromethylene) dibenzene (3.550 g, 17.515 mmol), and potassium carbonate (6.052 g, 43.787 mmol). A solution dissolved in N, N-dimethylformamide (10 mL) at room temperature was stirred at the same temperature for 17 hours. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. . The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge methanol / methylene chloride = 0% to 10%), the desired Formula 4-3 (0.798 g, 32.5%) as a white solid Got as.

Step 2: Synthesis of methyl 7-((2S, 6R) -4-benzhydryl-2,6-dimethylpiperazine-1-carboxamide) heptanoate (Formula 4-4)

To a solution of triphosgene (0.159 g, 0.535 mmol) and diisopropylamine (0.561 mL, 3.210 mmol) in methylene chloride (5 mL) at 0 ° C. was added methyl 7-aminoheptanoate hydrochloride (0.251 g, 1.284 mmol) was added and stirred at the same temperature. To the reaction mixture, Formula 4-3 (0.300 g, 1.070 mmol) prepared in Step 1 was added and further stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 30%), the desired Formula 4-4 (0.212 g, 42.6%) as a white solid Got as.

Step 3: Synthesis of (2S, 6R) -4-benzhydryl-N- (7- (hydroxyamino) -7-oxoheptyl) -2,6-dimethylpiperazine-1-carboxamide (Compound 1188)

  Formula 4-4 (0.100 g, 0.215 mmol), hydroxylamine (50.00% aqueous solution, 0.263 mL, 4.295 mmol), and potassium hydroxide (0.121 g, 2.148 mmol) prepared in Step 2. ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. After the solvent was removed from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the concentrate and the mixture was stirred. The precipitated solid was filtered, washed with water, dried and the desired compound 1188 ( 0.099 g, 98.8%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.51 (d, 4H, J = 7.5 Hz), 7.30 (t, 4H, J = 7.6 Hz), 7.19 (t, 2H, J = 7.3 Hz), 6.23 (t, 1H, J = 5.3 Hz), 4.23 (s, 1H), 3.94 (brs, 2H), 3.03-2.98 (m, 2H), 2.60 (d, 2H, J = 10.9 Hz), 1.96-1.90 ( m, 4H), 1.46-1.45 (m, 2H), 1.38-1.36 (m, 2H), 1.26-1.22 (m, 10H).

Example 4: Synthesis of compound 1189 Step 1: Synthesis of tert-butyl (R) -4-benzhydryl-2-methylpiperazine-1-carboxylate (Formula 4-5)

(R) -tert-butyl 2-methylpiperazine-1-carboxylate (1.000 g, 4.993 mmol), (chloromethylene) dibenzene (2.024 g, 9.986 mmol), and potassium carbonate (3.450 g, 24 .965 mmol) in N, N-dimethylformamide (10 mL) at room temperature was stirred at 80 ° C. for 17 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. . The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 10%), the desired compound 4-5 (0.813 g, 44.4%) as a white solid Got as.

Step 2: Synthesis of (R) -1-benzhydryl-3-methylpiperazine (Chemical Formula 4-6)

  Hydrochloric acid (4.00 M dioxane solution, 5.546 mL, 22.183 mmol) was added to a solution of the chemical formula 4-5 (0.813 g, 2.218 mmol) prepared in Step 1 in methylene chloride (10 mL) at room temperature. And stirred at the same temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Without further purification of the resulting material, the desired Formula 4-6 (0.590 g, 99.8%) was obtained as a white solid.

Step 3: Synthesis of methyl (R) -7- (4-benzhydryl-2-methylpiperazine-1-carboxamide) heptanoate (Formula 4-7)

To a solution of triphosgene (0.167 g, 0.563 mmol) and DIPEA (1.180 mL, 6.757 mmol) in methylene chloride (5 mL) at 0 ° C. was added methyl 7-aminoheptanoate hydrochloride (0.264 g, 1 .351 mmol) was added and stirred at the same temperature. Formula 4-6 (0.300 g, 1.126 mmol) prepared in Step 2 was added to the reaction mixture and further stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. The concentrate was column chromatography; after purification and concentration by (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 30%), the resulting material again chromatography (Waters, C _18; 1% formic acid Purify with (methanoic acid) aqueous solution / acetonitrile = 75% -5%, pass through an SPE cartridge (PL-HCO ₃ resin) and concentrate to the desired chemical formula 4-7 (0.106 g, 20.8%) Got.

Step 4: Synthesis of (R) -4-benzhydryl-N- (7- (hydroxyamino) -7-oxoheptyl) -2-methylpiperazine-1-carboxamide (Compound 1189)

  Formula 4-7 (0.100 g, 0.221 mmol), hydroxylamine (50.00% aqueous solution, 0.271 mL, 4.429 mmol), and potassium hydroxide (0.124 g, 2.214 mmol) prepared in Step 3. ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. After the solvent was removed from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the concentrate and the mixture was stirred. The precipitated solid was filtered, washed with water, dried and the desired compound 1189 ( 0.099 g, 98.8%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (brs, 2H), 7.45 (t, 4H, J = 6.3 Hz), 7.30 (t, 4H, J = 7.6 Hz), 7.19 (t, 2H, J = 6.8 Hz), 6.36-6.34 (m, 1H), 4.23 (s, 1H), 4.04 (brs, 1H), 3.62 (d, 1H, J = 12.4 Hz), 3.01-2.93 (m, 3H), 2.67 (d, 1H, J = 9.6 Hz), 2.60 (d, 1H, J = 10.8 Hz), 1.95 (dd, 1H, J = 11.0, 3.0 Hz), 1.88 (t, 2H, J = 7.3 Hz), 1.78 (t, 1H, J = 10.1 Hz), 1.44-1.43 (m, 2H), 1.36-1.35 (m, 2H), 1.20-1.18 (m, 7H).

Example 5: Synthesis of compound 1190 Step 1: Synthesis of tert-butyl (S) -4-benzhydryl-2-methylpiperazine-1-carboxylate (Formula 4-5)

(S) -tert-butyl 2-methylpiperazine-1-carboxylate (1.000 g, 4.993 mmol), (chloromethylene) dibenzene (2.024 g, 9.986 mmol), and potassium carbonate (3.450 g, 24 .965 mmol) in N, N-dimethylformamide (10 mL) at room temperature was stirred at 80 ° C. for 17 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. did. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 10%), the desired compound 4-5 (0.742 g, 40.5%) as a white solid Got as.

Step 2: Synthesis of (S) -1-benzhydryl-3-methylpiperazine (Chemical Formula 4-6)

  Hydrochloric acid (4.00 M dioxane solution, 5.061 mL, 20.246 mmol) was added to a solution of chemical formula 4-5 (0.742 g, 2.025 mmol) prepared in Step 1 in methylene chloride (10 mL) at room temperature. And stirred at the same temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material was used as is without further purification (0.530 g, 98.3%, white solid).

Step 3: Synthesis of methyl (S) -7- (4-benzhydryl-2-methylpiperazine-1-carboxamide) heptanoate (Formula 4-7)

To a solution of triphosgene (0.111 g, 0.375 mmol) and DIPEA (0.582 g, 4.505 mmol) in methylene chloride (5 mL) at 0 ° C. was added methyl 7-aminoheptanoate hydrochloride (0.176 g, 0 .901 mmol) was added and stirred at the same temperature. Chemical formula 4-6 (0.200 g, 0.751 mmol) prepared in Step 2 was added to the reaction mixture and further stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 30%), pale yellow desired Formula 4-7 (0.213 g, 62.8%) Obtained as an oil.

Step 4: Synthesis of (S) -4-benzhydryl-N- (7- (hydroxyamino) -7-oxoheptyl) -2-methylpiperazine-1-carboxamide (Compound 1190)

  Formula 4-7 (0.100 g, 0.221 mmol), hydroxylamine (50.00% aqueous solution, 0.271 mL, 4.429 mmol), and potassium hydroxide (0.124 g, 2.214 mmol) prepared in Step 3. ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. After the solvent was removed from the reaction mixture under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the concentrate and stirred. The precipitated solid was filtered, washed with water, dried and the desired compound 1190 ( 0.093 g, 92.8%) was obtained as a pale orange solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (brs, 2H), 7.45 (t, 4H, J = 6.3 Hz), 7.30 (t, 4H, J = 7.6 Hz), 6.35 (t, 1H, J = 5.5 Hz), 4.23 (s, 1H), 4.04 (brs, 1H), 3.62 (d, 1H, J = 12.6 Hz), 3.03-2.92 (m, 3H), 2.67 (d, 1H, J = 10.6 Hz), 2.60 (d, 1H, J = 11.2 Hz), 1.95 (dd, 1H, J = 11.1, 3.1 Hz), 1.88 (t, 2H, J = 7.4 Hz), 1.80-1.75 (m, 1H), 1.45-1.43 (m, 2H), 1.36-1.34 (m, 2H), 1.20-1.18 (m, 7H).

Example 6: Synthesis of compound 1209 Step 1: Synthesis of ethyl 1-benzhydrylpiperidine-4-carboxylate (Formula 5-2)

Ethyl piperidine-4-carboxylate (3.000 g, 19.083 mmol), (chloromethylene) dibenzene (5.802 g, 28.624 mmol), and potassium carbonate (13.187 g, 95.414 mmol) were combined with N, N-dimethyl. A solution dissolved in formamide (50 mL) was stirred at room temperature for 17 hours, further stirred at 80 ° C. for 3 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 40 g cartridge ethyl acetate / hexane = 0% to 15%), the desired Formula 5-2 (1.410g, 22.8%) as a colorless oil Got as.

Step 2: Synthesis of 1-benzhydrylpiperidine-4-carboxylic acid (Formula 5-3)

  A solution prepared by dissolving Formula 5-2 (1.410 g, 4.360 mmol) and LiOH (0.209 g, 8.719 mmol) prepared in Step 1 in methanol (10 mL) / water (5 mL) at room temperature at 60 ° C. After stirring for 17 hours, the temperature was lowered to room temperature to complete the reaction. After the solvent was removed from the reaction mixture under reduced pressure, 1N aqueous hydrochloric acid solution was added to neutralize, and the solvent was removed under reduced pressure. The resulting material was used as is without further purification (1.300 g, 101.0%, white solid).

Step 3: Synthesis of methyl 7- (1-benzhydrylpiperidine-4-carboxamide) heptanoate (Formula 5-4)

Formula 5-3 (1.500 g, 5.078 mmol) prepared in Step 2, methyl 7-aminoheptanoate hydrochloride (1.988 g, 10.156 mmol), EDC (1.947 g, 10.156 mmol), A solution of HBOt (1.372 g, 10.156 mmol) and diisopropylamine (4.435 mL, 25.391 mmol) in methylene chloride (30 mL) at room temperature was stirred at the same temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 40 g cartridge ethyl acetate / hexane = 0% to 40%), the desired Formula 5-4 (1.810g, 81.6%) as a colorless oil Got as.

Step 4: Synthesis of 1-benzhydryl-N- (7- (hydroxyamino) -7-oxoheptyl) piperidine-4-carboxamide (Compound 1209)

  Formula 5-4 (1.000 g, 2.290 mmol), hydroxylamine (50.00% aqueous solution, 2.802 mL, 45.809 mmol), and potassium hydroxide (1.285 g, 22.904 mmol) prepared in Step 3. ) In methanol (15 mL) at 0 ° C. was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The desired compound 1209 (1.000 g, 99.8%) was obtained as a pale orange solid without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (t, 1H, J = 5.4 Hz), 7.40 (d, 4H, J = 7.3 Hz), 7.27 (t, 4H, J = 7.5 Hz), 7.16 (t, 2H, J = 7.3 Hz), 4.25 (s, 1H), 2.98 (q, 2H, J = 6.4 Hz), 2.79 (d, 2H, J = 11.0 Hz), 2.09 − 2.02 (m, 1H) , 1.89 (t, 2H, J = 7.3 Hz), 1.77 (t, 2H, J = 9.8 Hz), 1.66 − 1.59 (m, 4H), 1.45 − 1.39 (m, 2H), 1.34 − 1.32 (m, 2H ), 1.29 - 1.27 (m, 4H); MS (ESI) m / z 438.2 (M + + H).

Example 7: Synthesis of compound 1210 Step 1: 1-((1H-imidazol-1-yl) sulfonyl) -3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Chemical Formula 8-3) )

  A solution of 1,1′-sulfonylbis (1H-imidazole) (5.000 g, 25.227 mmol) and methyl trifluoromethanesulfonate (2.855 mL, 25.227 mmol) in methylene chloride (100 mL) at room temperature, Stir at the same temperature for 3 hours. The precipitated solid was filtered and dried to obtain the desired chemical formula 8-3 (5.160 g, 45.3%) as a pale yellow solid.

Step 2: Synthesis of (1-((1H-imidazol-1-yl) sulfonyl) piperidin-4-yl) diphenylmethanol (Chemical Formula 8-4)

A solution of diphenyl (piperidin-4-yl) methanol (1.000 g, 3.740 mmol) and chemical formula 8-3 (2.033 g, 5.610 mmol) prepared in Step 1 in acetonitrile (20 mL) at room temperature was prepared. And stirred at the same temperature for 17 hours. The reaction mixture solvent was removed under reduced pressure, the concentrate was purified by column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 40%), the desired Formula 8-4 ( 0.487 g, 32.8%) was obtained as a white solid.

Step 3: Synthesis of (1-((3-methyl-1H-34-imidazol-1-yl) sulfonyl) piperidin-4-yl) diphenylmethanol trifluoromethanesulfonate (Formula 8-5)

  A solution of Formula 8-4 (0.487 g, 1.225 mmol) prepared in Step 2 and methyl trifluoromethanesulfonate (0.146 mL, 1.286 mmol) in methylene chloride (10 mL) at 0 ° C. was added at room temperature. For 2 hours. The precipitated solid was filtered, washed with methylene chloride and dried to give the desired chemical formula 8-5 (0.670 g, 97.4%) as a white solid.

Step 4: Synthesis of methyl 7-((4- (hydroxydiphenylmethyl) piperidine) -1-sulfonamido) heptanoate (Formula 8-6)

A solution of Formula 8-5 (0.504 g, 0.897 mmol) and methyl 7-aminoheptanoate hydrochloride (0.228 g, 1.167 mmol) prepared in Step 3 in acetonitrile (3 mL) at 80 ° C. Was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 10% to 60%), the desired Formula 8-6 (0.147 g, 33.5%) as a white solid Got as.

Step 5: Synthesis of N-hydroxy-7-((4- (hydroxydiphenylmethyl) piperidine) -1-sulfonamido) heptanamide (Compound 1210)

  Formula 8-6 (0.150 g, 0.307 mmol), potassium hydroxide (0.172 g, 3.070 mmol), and hydroxyamine (50.00% solution, 0.188 mL, 3.070 mmol) prepared in Step 4 ) In methanol (1 mL) at room temperature was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Without further purification of the resulting material, the desired compound 1210 (0.067 g, 44.6%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 8.68 (s, 1H), 7.52 (d, 4H, J = 7.4 Hz), 7.26 (t, 4H, J = 7.6 Hz) , 7.12 (m, 3H), 3.46 (m, 2H), 2.82 (m, 2H), 2.63 (m, 3H), 1.93 (t, 2H, J = 7.3 Hz), 1.48-1.22 (m, 13H); MS (ESI) m / z 490.6 (M + + H).

Example 8: Synthesis of compound 1213 Step 1: Synthesis of methyl 7- (4-benzhydryl-N-methylpiperazine-1-carboxamide) heptanoate (Formula 1-4)

Methyl 7- (4-benzhydrylpiperazine-1-carboxamide) heptanoate (0.100 g, 0.229 mmol) and sodium hydride (60.00%, 0.046 g, 1.143 mmol) at 0 ° C. with N, N -Iodomethane (0.071 mL, 1.143 mmol) was added to a solution in dimethylformamide (3 mL) and stirred at the same temperature for 10 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridge ethyl acetate / hexane = 10% to 40%), the desired Formula 1-4 (0.097 g, 94.0%) as a colorless oil Got as.

Step 2: Synthesis of 4-benzhydryl-N- (7- (hydroxyamino) -7-oxoheptyl) -N-methylpiperazine-1-carboxamide (Compound 1213)

  Formula 1-4 prepared in Step 1 (0.097 g, 0.215 mmol), hydroxylamine (50.00% aqueous solution, 0.263 mL, 4.296 mmol), and potassium hydroxide (0.121 g, 2.148 mmol) ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. Without further purification of the resulting material, the desired compound 1213 (0.010 g, 10.3%) was obtained as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.44 (d, 4H, J = 7.4 Hz), 7.27 (t, 4H, J = 7.5 Hz), 7.17 (t, 2H, J = 7.3 Hz), 4.26 ( s, 1H), 3.24-3.22 (m, 4H), 3.17 (t, 2H, J = 7.2 Hz), 2.81 (s, 3H), 2.41-2.38 (m, 4H), 2.07 (t, 2H, J = 7.4 Hz), 1.62-1.52 (m, 4H), 1.33-1.24 (m, 4H); MS (ESI) m / z 453.4 (M ⁺ + H).

Example 9: Synthesis of compound 1221 Step 1: Synthesis of N, N-diphenylpiperidin-4-amine hydrochloride (Formula 6-4)

  To a solution of tert-butyl 4- (diphenylamino) piperidine-1-carboxylate (1.000 g, 2.837 mmol) in methylene chloride (10 mL) at room temperature was added hydrochloric acid (4.00 M 1,4-dioxane solution, 3 546 mL, 14.185 mmol) was added and stirred at the same temperature for 17 hours. The precipitated solid was filtered, washed with methylene chloride and dried to give the desired chemical formula 6-4 (0.800 g, 97.6%) as a white solid.

Step 2: Synthesis of N, N-diphenylpiperidin-4-amine (Formula 6-5)

  Saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to a solution of Formula 6-4 (0.600 g, 2.077 mmol) prepared in Step 1 in water (5 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. . Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material was used as is without further purification (0.496 g, 94.6%, colorless oil).

Step 3: Synthesis of methyl 7-(-4- (diphenylamino) piperidine-1-carboxamide) heptanoate (Formula 6-6)

Formula 6-5 prepared in Step 2 (0.100 g, 0.396 mmol), methyl 7-aminoheptanoate hydrochloride (0.078 g, 0.396 mmol), triphosgene (0.059 g, 0.198 mmol), A solution of DIPEA (0.415 mL, 2.378 mmol) in methylene chloride (3 mL) at 0 ° C. was stirred at the same temperature for 1 hour, and then saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture at 0 ° C. The reaction was completed after stirring for 10 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridge ethyl acetate / hexane = 10% to 60%), pale yellow desired Formula 6-6 (0.096 g, 55.4%) Obtained as an oil.

Step 4: Synthesis of 4- (diphenylamino) -N- (7- (hydroxyamino) -7-oxoheptyl) piperidine-1-carboxamide (Compound 1221)

  Formula 6-6 (0.096 g, 0.219 mmol), hydroxylamine (50.00% aqueous solution, 0.268 mL, 4.388 mmol), and potassium hydroxide (0.123 g, 2.194 mmol) prepared in Step 3. ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. After removing the solvent from the reaction mixture under reduced pressure, saturated sodium bicarbonate aqueous solution (20 mL) and methylene chloride (5 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with water, and dried. The desired compound 1221 (0.076 g, 79.0%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.27 (t, 4H, J = 7.8 Hz), 6.97 (t, 2H, J = 7.2 Hz), 6.79 (d, 4H, J = 7.8 Hz), 6.35 (t, 1H, J = 5.4 Hz), 4.10-4.04 (m, 1H), 3.97 (d, 2H, J = 13.1 Hz), 2.90 (q, 2H, J = 6.4 Hz), 2.78 (t, 2H, J = 12.5 Hz), 1.90 (t, 2H, J = 7.3 Hz), 1.84 (d, 2H, J = 12.5 Hz), 1.46-1.39 (m, 2H), 1.31-1.27 (m, 2H), 1.17- 1.10 (m, 4H), 1.08-1.01 (m, 2H).

Example 10: Synthesis of compound 1222 Step 1: Synthesis of di (pyridin-2-yl) methanol (Formula 3-2)

To a solution of di (pyridin-2-yl) methanone (2.000 g, 10.858 mmol) in methanol (20 mL) at 0 ° C. was added NaBH ₄ (0.452 g, 11.944 mmol), and the same temperature was maintained for 1 hour. After stirring, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture at 0 ° C., and the reaction was terminated by stirring for 10 minutes. Water was poured into the reaction mixture and extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Without further purification of the resulting material, the desired Formula 3-2 (2.000 g, 98.9%) was obtained as a red oil.

Step 2: Synthesis of di (pyridin-2-yl) methylmethanesulfonate (Formula 3-3)

Formula 3-2 (1.000 g, 5.370 mmol), methanesulfonyl chloride (0.623 mL, 8.055 mmol), and triethylamine (2.246 mL, 16.111 mmol) prepared in Step 1 were added at 0 ° C. to methylene chloride. The solution dissolved in (10 mL) was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 30%), pink desired Formula 3-3 (0.670 g, 47.2%) Obtained as a solid.

Step 3: Synthesis of methyl 7- (4- (di (pyridin-2-yl) methyl) piperazine-1-carboxamide) heptanoate (Formula 3-4)

Chemical formula 3-3 (0.258 g, 0.975 mmol), chemical formula 2-5 (0.200 g, 0.650 mmol), and potassium carbonate (0.449 g, 3.249 mmol) prepared in Step 2 were mixed with N at room temperature. , N-dimethylformamide (4 mL) was stirred at 80 ° C. for 17 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridges methanol / methylene chloride = 0% to 10%), orange desired Formula 3-4 (0.255 g, 89.3%) Obtained as an oil.

Step 4: Synthesis of 4- (di (pyridin-2-yl) methyl) -N- (7- (hydroxyamino) -7-oxoheptyl) piperazine-1-carboxamide (Compound 1222)

Formula 3-4 (0.255 g, 0.580 mmol), hydroxylamine (50.00% aqueous solution, 0.710 mL, 11.603 mmol) and potassium hydroxide (0.326 g, 5.801 mmol) prepared in Step 3. ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. After the solvent was removed from the reaction mixture under reduced pressure, the concentrate was purified by column chromatography (Waters, C ₁₈ ; 1% formic acid (methanoic acid) aqueous solution / acetonitrile aqueous solution = 70% to 5%), and the SPE cartridge ( PL-HCO ₃ resin) and concentrated to give the desired compound 1222 (0.051 g, 20.0%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (dt, 2H, J = 4.8, 0.8 Hz), 7.77 (td, 2H, J = 7.7, 1.7 Hz), 7.62 (d, 2H, J = 7.8 Hz), 7.25-7.22 (m, 2H), 6.40 (t, 1H, J = 5.2 Hz), 4.64 (s, 1H), 3.28-3.27 (m, 4H), 2.96 (q, 2H, J = 6.6 Hz ), 2.25 (t, 4H, J = 4.7 Hz), 1.92 (t, 2H, J = 7.3 Hz), 1.48-1.43 (m, 2H), 1.35-1.33 (m, 2H), 1.21-1.20 (m, 4H).

Example 11: Synthesis of compound 1223 Step 1: Synthesis of tert-butyl 4-((7-methoxy-7-oxoheptyl) carbamoyl) piperazine-1-carboxylate (Formula 2-2)

To a solution of triphosgene (4.780 g, 16.107 mmol) and diisopropylamine (16.879 mL, 96.644 mmol) in methylene chloride (100 mL) at 0 ° C. was added methyl 7-aminoheptanoate hydrochloride (6.304 g, 32.215 mmol) was added and stirred at the same temperature. To the reaction mixture was added tert-butylpiperazine-1-carboxylate (6.0000 g, 32.215 mmol), and the mixture was further stirred at the same temperature for 1 hour, and then saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the reaction mixture at 0 ° C. The reaction was terminated by stirring for 10 minutes. Water was poured into the reaction mixture and extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 80 g cartridge methanol / methylene chloride = 0% to 5%), a pale yellow desired Formula 2-2 (3.430g, 28.7%) Obtained as an oil.

Step 2: Synthesis of methyl 7- (piperazine-1-carboxamide) heptanoate hydrochloride (formula 2-5)

  Hydrochloric acid (4.00 M dioxane solution, 11.542 mL, 46.167 mmol) was added to a solution of the chemical formula 2-2 (3.430 g, 9.233 mmol) prepared in Step 1 in methylene chloride (50 mL) at room temperature. And stirred at the same temperature for 17 hours. After the solvent was removed from the reaction mixture under reduced pressure, ethyl acetate (50 mL) was added to the concentrate and the mixture was stirred. The precipitated solid was filtered, washed with ethyl acetate, and dried to obtain the desired chemical formula 2-5. (2.300 g, 80.9%) was obtained as a white solid.

Step 3: Synthesis of 4,4 ′-(chloromethylene) bis (fluorobenzene) (Formula 2-4)

  A solution of bis (4-fluorophenyl) methanol (5.000 g, 22.706 mmol) in methylene chloride (50 mL) was stirred at room temperature for 4 hours, thionyl chloride (1.812 mL, 24.976 mmol) was added, and 40 After further stirring at 2 ° C. for 2 hours, the temperature was lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the resulting material was obtained without further purification to give the desired Formula 2-4 (5.350 g, 98.7%) as an orange oil.

Step 4: Synthesis of methyl 7- (4- (bis (4-fluorophenyl) methyl) piperazine-1-carboxamide) heptanoate (Formula 2-6)

Formula 2-4 (0.233 g, 0.975 mmol), methyl 7- (piperazine-1-carboxamido) heptanoate hydrochloride (0.200 g, 0.650 mmol), and potassium carbonate (0 A solution prepared by dissolving .449 g, 3.249 mmol) in N, N-dimethylformamide (4 mL) at room temperature was stirred at 80 ° C. for 17 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridges methanol / methylene chloride = 0% to 10%), pale brown desired Formula 2-6 (0.101 g, 32.8%) Obtained as an oil.

Step 5: Synthesis of 4- (bis (4-fluorophenyl) methyl) -N- (7- (hydroxyamino) -7-oxoheptyl) piperazine-1-carboxamide (Compound 1223)

Formula 2-6 (0.101 g, 0.213 mmol), hydroxylamine (50.00% aqueous solution, 0.261 mL, 4.266 mmol), and potassium hydroxide (0.120 g, 2.133 mmol) prepared in Step 4. ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. After the solvent was removed from the reaction mixture under reduced pressure, the concentrate was purified by a column chromatography method (Waters, C ₁₈ ; 1% formic acid (methanoic acid) aqueous solution / acetonitrile = 70% to 5%), and the SPE cartridge (PL -HCO ₃ resin) and concentrated to give the desired compound 1223 (0.002 g, 2.0%) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.44 (m, 4H), 7.04 (t, 4H, J = 8.8 Hz), 6.44 (t, 1H, J = 5.3 Hz), 4.31 (s, 1H ), 3.39 (t, 4H, J = 5.0 Hz), 3.16-3.12 (m, 2H), 2.36 (t, 4H, J = 5.0 Hz), 2.09 (t, 2H, J = 7.4 Hz), 1.64-1.61 (m, 2H), 1.51 - 1.48 (m, 2H), 1.35 - 1.33 (m, 4H); MS (ESI) m / z 475.3 (M + + H).

Example 12: Synthesis of compound 1224 Step 1: Synthesis of 4,4 '-(chloromethylene) bis (chlorobenzene) (Formula 2-4)

  Thionyl chloride (3.153 mL, 43.458 mmol) was added to a solution of bis (4-chlorophenyl) methanol (10.000 g, 39.507 mmol) in methylene chloride (100 mL) at 0 ° C., and the mixture was stirred at room temperature for 5 hours. . After removing the solvent from the reaction mixture under reduced pressure, the resulting material was obtained without further purification to give the desired compound of Formula 2-4 (10.700 g, 99.7%) as a white solid.

Step 2: Synthesis of methyl 7- (4- (bis (4-chlorophenyl) methyl) piperazine-1-carboxamide) heptanoate (Formula 2-6)

The chemical formula 2-4 (0.265 g, 0.975 mmol), chemical formula 2-5 (0.200 g, 0.650 mmol), and potassium carbonate (0.449 g, 3.249 mmol) prepared in Step 1 were mixed with N at room temperature. , N-dimethylformamide (4 mL) was stirred at 80 ° C. for 17 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridges methanol / methylene chloride = 0% to 10%), the desired Formula 2-6 (0.271 g, 82.4%) as a pale yellow Obtained as an oil.

Step 3: Synthesis of 4- (bis (4-chlorophenyl) methyl) -N- (7- (hydroxyamino) -7-oxoheptyl) piperazine-1-carboxamide (Compound 1224)

Formula 2-6 (0.271 g, 0.535 mmol), hydroxylamine (50.00% aqueous solution, 0.655 mL, 10.702 mmol), and potassium hydroxide (0.300 g, 5.351 mmol) prepared in Step 2 ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. After the solvent was removed from the reaction mixture under reduced pressure, the concentrate was purified by a column chromatography method (Waters, C ₁₈ ; 1% formic acid (methanoic acid) aqueous solution / acetonitrile = 70% to 5%), and the SPE cartridge (PL -HCO ₃ resin) and concentrated to give the desired compound 1224 (0.035 g, 12.9%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (brs, 1H), 8.69 (brs, 1H), 7.43 (d, 4H, J = 8.6 Hz), 7.37 (d, 4H, J = 8.4 Hz) , 6.41 (t, 1H, J = 5.3 Hz), 4.40 (s, 1H), 3.28-3.27 (m, 4H), 2.96 (q, 2H, J = 6.4 Hz), 2.22-2.21 (m, 4H), 1.92 (t, 2H, J = 7.4 Hz), 1.48-1.44 (m, 2H), 1.37-1.35 (m, 2H), 1.24-1.21 (m, 4H); MS (ESI) m / z 507.4 (M ⁺ + H).

Example 13: Synthesis of compound 1240 Step 1: Synthesis of methyl 8- (4-benzhydrylpiperazine-1-carboxamide) octanoate (Formula 1-3)

To a solution of triphosgene (0.118 g, 0.396 mmol) and diisopropylamine (0.830 mL, 4.755 mmol) in methylene chloride (5 mL) at 0 ° C. was added methyl 8-aminooctanoate hydrochloride (0.166 g, 0.793 mmol) was added and stirred for 1 hour. To the reaction mixture was added the starting material (0.200 g, 0.793 mmol) and stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and aqueous solution layer, and then concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridge ethyl acetate / hexane = 10% to 70%), pale yellow desired Formula 1-3 (0.158 g, 44.1%) Obtained as a solid.

Step 2: Synthesis of 4-benzhydryl-N- (8- (hydroxyamino) -8-oxoethyl) piperazine-1-carboxamide (Compound 1240)

  Formula 1-3 (0.158 g, 0.350 mmol), hydroxylamine (50.00% aqueous solution, 0.428 mL, 6.997 mmol), and potassium hydroxide (0.196 g, 3.499 mmol) prepared in Step 1 ) In methanol (3 mL) at room temperature was stirred at the same temperature for 30 minutes. The solvent was removed from the reaction mixture under reduced pressure, and the concentrate was stirred with saturated aqueous sodium hydrogen carbonate (20 mL). The precipitated solid was filtered, washed with water, dried and dried to give the desired compound 1240 ( 0.074 g, 46.7%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (brs, 2H), 7.43 (d, 4H, J = 7.5 Hz), 7.30 (t, 4H, J = 7.6 Hz), 7.19 (t, 2H, J = 7.3 Hz), 6.42 (t, 1H, J = 5.2 Hz), 4.29 (s, 1H), 3.28-3.27 (m, 4H), 2.97 (q, 2H, J = 6.4 Hz), 2.23-2.22 ( m, 4H), 1.90 (t, 2H, J = 7.3 Hz), 1.47-1.44 (m, 2H), 1.37-1.34 (m, 2H), 1.22 (brs, 4H); MS (ESI) m / z 453.6 (M ⁺⁺ H).

Example 14: Synthesis of compound 1241 Step 1: Synthesis of methyl 7- (4- (1-phenylethyl) piperazine-1-carboxamido) heptanoate (Formula 9-2)

A solution of Formula 2-5 (0.150 g, 0.553 mmol) and acetophenone (0.100 g, 0.829 mmol) in methylene chloride (3 mL) was stirred at room temperature for 10 minutes, and NaBH (OAc) ₃ (0. 234 g, 1.106 mmol) was added and further stirred at the same temperature for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridges methanol / methylene chloride = 0% to 5%), the desired Formula 9-2 (0.038 g, 18.3%) as a colorless oil Got as.

Step 2: Synthesis of N- (7- (hydroxyamino) -7-oxoheptyl) -4- (1-phenylethyl) piperazine-1-carboxamide (Compound 1241)

  Formula 9-2 (0.038 g, 0.101 mmol), hydroxylamine (50.00% aqueous solution, 0.124 mL, 2.024 mmol), and potassium hydroxide (0.057 g, 1.012 mmol) prepared in Step 1 ) In methanol (3 mL) at room temperature was stirred at the same temperature for 30 minutes. To the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was poured, extracted with methylene chloride, and then filtered through a plastic filter to remove the solid residue and the aqueous solution layer. Concentrated under reduced pressure. The desired compound 1241 (0.013 g, 34.1%) was obtained as a pale orange solid without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.32-7.30 (m, 4H), 7.26-7.23 (m, 1H), 3.71-3.34 (m, 5H), 3.11 (t, 2 H, J = 7.1 Hz), 2.50-2.45 (m, 2H), 2.37-2.32 (m, 2H), 2.05 (t, 2H, J = 7.4 Hz), 1.61-1.56 (m, 2H), 1.49-1.44 (m, 2H) , 1.37 (d, 3H, J = 7.6 Hz), 1.33 - 1.29 (m, 4H); MS (ESI) m / z 477.2 (M + + H).

Example 15: Synthesis of compound 1243 Step 1: Synthesis of ethyl 1- (1-phenylethyl) piperidine-4-carboxylate (Formula 10-2)

STAB (2.408 g, 11.361 mmol) was added to a solution of acetophenone (1.050 g, 8.739 mmol) and ethyl piperidine-4-carboxylate (1.751 mL, 11.361 mmol) in methylene chloride (10 mL) at room temperature. And stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 50%), the desired formula 10-2 (0.700 g, 30.6%) as a colorless oil Got as.

Step 2: Synthesis of 1- (1-phenylethyl) piperidine-4-carboxylic acid (Chemical Formula 10-3)

  A solution prepared by dissolving Formula 10-2 (0.700 g, 2.678 mmol) and LiOH (0.096 g, 4.017 mmol) prepared in Step 1 in methanol (3 mL) / water (1 mL) at 40 ° C. is the same. After stirring at temperature for 5 hours to lower the temperature to room temperature, 1M HCl was added to the reaction mixture at 0 ° C. and stirred for 10 minutes to complete the reaction. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material was used as is without further purification (0.500 g, 69.2%, white foamy solid).

Step 3: Synthesis of methyl 7- (1- (1-phenylethyl) piperidine-4-carboxamide) heptanoate (Formula 10-4)

Formula 10-3 (0.300 g, 1.286 mmol) prepared in Step 2, methyl 7-aminoheptanoate hydrochloride (0.503 g, 2.572 mmol), EDC (0.493 g, 2.572 mmol), A solution of HOBt (0.347 g, 2.572 mmol) and diisopropylamine (1.123 mL, 6.429 mmol) in methylene chloride (4 mL) / N, N-dimethylformamide (1 mL) at room temperature was added at the same temperature. Stir for 17 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridges methanol / methylene chloride = 0% to 10%), the desired formula 10-4 (0.122 g, 25.3%) as a brown oil Got as.

Step 4: Synthesis of N- (7- (hydroxyamino) -7-oxoheptyl) -1- (1-phenylethyl) piperidine-4-carboxamide (Compound 1243)

  Chemical formula 10-4 (0.122 g, 0.326 mmol), hydroxylamine (50.00% aqueous solution, 0.398 mL, 6.515 mmol) and potassium hydroxide (0.183 g, 3.257 mmol) prepared in Step 3. ) In methanol (3 mL) at room temperature was stirred at the same temperature for 30 minutes. To the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was poured, extracted with methylene chloride, and then filtered through a plastic filter to remove the solid residue and the aqueous solution layer. Concentrated under reduced pressure. The desired compound 1243 (0.074 g, 60.5%) was obtained as an orange solid without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (brs, 1H), 8.71 (brs, 1H), 7.64 (t, 1H, J = 5.6 Hz), 7.32-7.27 (m, 4H), 7.23- 7.20 (m, 1H), 3.40 - 3.37 (m, 1H), 3.00 - 2.95 (m, 3H); MS (ESI) m / z 376.3 (M + + H).

Example 16: Synthesis of compound 1256 Step 1: Synthesis of methyl 7- (1-benzhydryl-N-methylpiperidine-4-carboxamide) heptanoate (Formula 5-5)

Methyl 7- (1-benzhydrylpiperidine-4-carboxamide) heptanoate (0.200 g, 0.458 mmol) and sodium hydride (60.00%, 0.092 g, 2.290 mmol) were combined with N, N-dimethylformamide. The solution dissolved in (5 mL) was stirred at room temperature for 10 minutes, iodomethane (0.143 mL, 2.290 mmol) was added and further stirred at the same temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 4g cartridge ethyl acetate / hexane = 10% to 70%), pale yellow desired Formula 5-5 (0.089 g, 43.1%) Obtained as an oil.

Step 2: Synthesis of 1-benzhydryl-N- (7- (hydroxyamino) -7-oxoheptyl) -N-methylpiperidine-4-carboxamide (Compound 1256)

  Formula 5-5 (0.089 g, 0.198 mmol), hydroxylamine (50.00% aqueous solution, 0.242 mL, 3.950 mmol), and potassium hydroxide (0.111 g, 1.975 mmol) prepared in Step 1. ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. To the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was poured, extracted with methylene chloride, and then filtered through a plastic filter to remove the solid residue and the aqueous solution layer. Concentrated under reduced pressure. The desired compound 1256 (0.089 g, 99.8%) was obtained as a white solid without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (brs, 2H), 7.40 (d, 4H, J = 7.2 Hz), 7.29 (t, 4H, J = 7.6 Hz), 7.18 (t, 2H, J = 7.3 Hz), 4.30 (s, 1H), 3.23 (q, 2H, J = 7.5 Hz), 2.94 (s, 2H), 2.81 (d, 2H, J = 11.4 Hz), 2.76 (s, 1H) , 1.91-1.83 (m, 4H), 1.69-1.53 (m, 4H), 1.46-1.37 (m, 4H), 1.24-1.19 (m, 4H); MS (ESI) m / z 452.6 (M ⁺ + H ).

Example 17: Synthesis of compound 1257 Step 1: Synthesis of methyl 6- (4-benzhydrylpiperazine-1-carboxamido) hexanoate (Formula 1-3)

To a solution of triphosgene (0.294 g, 0.991 mmol) and diisopropylamine (2.076 mL, 11.888 mmol) in methylene chloride (10 mL) at 0 ° C. was added methyl 6-aminohexanoate hydrochloride (0.360 g). 1.981 mmol) was added and stirred at the same temperature. 1-Benzhydrylpiperazine (0.500 g, 1.981 mmol) was added to the reaction mixture and further stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 40%), the desired Formula 1-3 (0.320 g, 38.1%) as a yellow oil Got as.

Step 2: Synthesis of 4-benzhydryl-N- (6- (hydroxyamino) -6-oxohexyl) piperazine-1-carboxamide (Compound 1257)

  Formula 1-3 (0.200 g, 0.472 mmol), hydroxylamine (50.00% aqueous solution, 0.578 mL, 9.444 mmol), and potassium hydroxide (0.265 g, 4.722 mmol) prepared in Step 1. ) In methanol (5 mL) at room temperature was stirred at the same temperature for 1 hour. To the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was poured, extracted with methylene chloride, and then filtered through a plastic filter to remove the solid residue and the aqueous solution layer. Concentrated under reduced pressure. The desired compound 1257 (0.049 g, 24.4%) was obtained as a pale yellow solid without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.43 (d, 4H, J = 7.2 Hz), 7.30 (t, 4H, J = 7.6 Hz), 7.19 (t, 2H, J = 7.3 Hz), 6.42 (t, 1H, J = 5.4 Hz), 4.29 (s, 1H), 3.27 (t, 4H, J = 4.5 Hz), 2.96 (q, 2H, J = 6.4 Hz), 2.23 (t, 4H, J = 4.6 Hz), 1.90 (t, 2H, J = 7.4 Hz), 1.47-1.44 (m, 2H), 1.38-1.34 (m, 2H), 1.20-1.16 (m, 2H); MS (ESI) m / z 425.5 (M ⁺⁺ H).

Example 18: Synthesis of compound 1316 Step 1: Synthesis of methyl 6- (1-benzhydrylpiperidine-4-carboxamido) hexanoate (Formula 5-4)

Chemical formula 5-3 (0.300 g, 1.016 mmol), methyl 6-aminohexanoate hydrochloride (0.369 g, 2.031 mmol), EDC (0.389 g, 2.031 mmol), HOBt (0.274 g, 2.031 mmol) and diisopropylamine (0.887 mL, 5.078 mmol) in methylene chloride (3 mL) / N, N-dimethylformamide (0.5 mL) at room temperature were stirred at the same temperature for 17 hours. . Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 30%), pale yellow desired Formula 5-4 (0.161 g, 37.5%) Obtained as an oil.

Step 2: Synthesis of 1-benzhydryl-N- (6- (hydroxyamino) -6-oxohexyl) piperidine-4-carboxamide (Compound 1316)

Formula 5-4 (0.161 g, 0.381 mmol), hydroxylamine (50.00% aqueous solution, 0.466 mL, 7.620 mmol), and potassium hydroxide (0.214 g, 3.810 mmol) prepared in Step 1 ) In methanol (3 mL) at room temperature was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The desired compound 1316 (0.056 g, 34.7%) was obtained as a white solid without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.33 (brs, 1H), 8.66 (brs, 1H), 7.70 (t, 1H, J = 5.6 Hz), 7.41 (d, 4H, J = 7.4 Hz ), 7.17 (t, 2H, J = 7.4 Hz), 4.26 (s, 2H), 2.99 to 2.28 (m, 2H), 2.80 (d, 2H, J = 11.5 Hz), 2.09 to 2.02 (m, 1H) , 1.91 (t, 2H, J = 7.5 Hz), 1.80 to 1.75 (m, 2H), 1.68 to 1.59 (m, 4H).

Example 19: Synthesis of compound 1317 Step 1: Synthesis of methyl 8- (1-benzhydrylpiperidine-4-carboxamido) octanoate (Formula 5-4)

Chemical formula 5-3 (0.300 g, 1.016 mmol), methyl 8-aminooctanoate hydrochloride (0.426 g, 2.031 mmol), EDC (0.389 g, 2.031 mmol), HOBt (0.274 g, 2.031 mmol) and diisopropylamine (0.887 mL, 5.078 mmol) in methylene chloride (3 mL) / N, N-dimethylformamide (0.5 mL) at room temperature were stirred at the same temperature for 17 hours. . Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 30%), the desired Formula 5-4 (0.220 g, 49.6%) as a colorless oil Got as.

Step 2: Synthesis of 1-benzhydryl-N- (8- (hydroxyamino) -8-oxoethyl) piperidine-4-carboxamide (Compound 1317)

  Formula 5-4 (0.220 g, 0.488 mmol), hydroxylamine (50.00% aqueous solution, 0.597 mL, 9.764 mmol) and potassium hydroxide (0.274 g, 4.882 mmol) prepared in Step 1. ) In methanol (5 mL) at room temperature was stirred at the same temperature for 1 hour. After the solvent was removed from the reaction mixture under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the concentrate and stirred. The precipitated solid was filtered, washed with water, dried and the desired compound 1317 ( 0.189 g, 85.7%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (brs, 2H), 7.73 (t, 1H, J = 5.3 Hz), 7.41 (d, 4H, J = 8.0 Hz), 7.28 (t, 4H, J = 7.5 Hz), 7.17 (t, 2H, J = 7.3 Hz), 4.26 (s, 1H), 2.99 (q, 2H, J = 6.4 Hz), 2.80 (d, 2H, J = 11.1 Hz), 2.10 -2.04 (m, 1H), 1.87 (t, 2H, J = 7.3 Hz), 1.78 (t, 2H, J = 10.0 Hz), 1.67-1.56 (m, 4H), 1.46-1.42 (m, 2H), 1.36-1.33 (m, 2H), 1.21 (brs, 6H).

Example 20: Synthesis of compound 1647 Step 1: Synthesis of 2,2 '-(chloromethylene) bis (fluorobenzene) (Formula 2-4)

To a solution of bis (2-fluorophenyl) methanol (0.500 g, 2.270 mmol) and triethylamine (0.348 mL, 2.498 mmol) in methylene chloride (5 mL) at room temperature, methanesulfonyl chloride (0.193 mL, 2 498 mmol) and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 5%), the desired compound of formula 2-4 (0.290 g, 53.5%) Obtained as a colorless oil.

Step 2: Synthesis of methyl 7- (4- (bis (2-fluorophenyl) methyl) piperazine-1-carboxamide) heptanoate (Formula 2-6)

Compound of formula 2-4 prepared in Step 1 (0.448 g, 1.877 mmol), methyl 7- (piperazin-1-yl) heptanoate hydrochloride (0.746 g, 2.816 mmol), and potassium carbonate A solution prepared by dissolving (1.297 g, 9.386 mmol) in N, N-dimethylformamide (8 mL) at 80 ° C. was stirred at the same temperature for 16 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 60%), the desired compound of formula 2-6 (0.170 g, 19.1%) Obtained as a light yellow solid.

Step 3: Synthesis of 4- (bis (2-fluorophenyl) methyl) -N- (7- (hydroxyamino) -7-oxoheptyl) piperazine-1-carboxamide (Compound 1647)

  The compound of Formula 2-6 prepared in Step 2 (0.200 g, 0.422 mmol) and hydroxylamine (50.00% aqueous solution, 0.258 mL, 4.223 mmol) were dissolved in methanol (5 mL) at 0 ° C. The solution was stirred at room temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, methanol (10 mL) and saturated aqueous sodium hydrogen carbonate solution (90 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with water, and dried. The desired compound 1647 (0.200 g, 99.8%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.59-7.55 (m, 2H), 7.31-7.26 (m, 2H), 7.23-7.19 (m, 2H), 7.16-7.11 (m, 2H), 6.42 (t, 1H, J = 5.5 Hz), 4.96 (s, 1H), 3.29-3.28 (m, 4H), 2.99-2.94 (m, 2H), 2.28-2.26 (m, 4H), 1.93-1.89 (m , 2H), 1.47 - 1.43 ( m, 2H), 1.37 - 1.33 (m, 2H), 1.19 - 1.20 (m, 4H); MS (ESI) m / z 475.4 (M + + H).

Example 21: Synthesis of compound 1648 Step 1: Synthesis of 3,3 '-(chloromethylene) bis (fluorobenzene) (Formula 2-4)

To a solution of bis (3-fluorophenyl) methanol (1.000 g, 4.541 mmol) and triethylamine (0.696 mL, 4.995 mmol) in methylene chloride (10 mL) at room temperature, methanesulfonyl chloride (0.387 mL, 4 .995 mmol) and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 5%), the desired compound of formula 2-4 (0.670 g, 61.8%) Obtained as a colorless oil.

Step 2: Synthesis of 7- (4- (bis (3-fluorophenyl) methyl) piperazine-1-carboxamide) heptanoate (Formula 2-6)

Compound of formula 2-4 prepared in step 1 (0.670 g, 2.807 mmol), methyl 7- (piperazin-1-yl) heptanoate hydrochloride (1.115 g, 4.21 mmol), and potassium carbonate A solution prepared by dissolving (1.940 g, 14.037 mmol) in N, N-dimethylformamide (10 mL) at 80 ° C. was stirred at the same temperature for 16 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 24 g cartridge ethyl acetate / hexane = 0% to 50%), the desired compound of formula 2-6 (0.294 g, 22.1%) Obtained as a white solid.

Step 3: Synthesis of 4- (bis (3-fluorophenyl) methyl) -N- (7- (hydroxyamino) -7-oxoheptyl) piperazine-1-carboxamide (Compound 1648)

  The compound of formula 2-6 (0.100 g, 0.211 mmol) prepared in Step 2 and hydroxylamine (50.00% aqueous solution, 0.129 mL, 2.112 mmol) were dissolved in methanol (3 mL) at 0 ° C. The solution was stirred at room temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, methanol (10 mL) and saturated aqueous sodium hydrogen carbonate solution (90 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with water, dried, The desired compound 1648 (0.097 g, 97.1%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 8.72 (s, 1H), 7.38-7.33 (m, 2H), 7.28-7.25 (m, 4H), 7.06-7.01 (m , 2H), 6.40 (t, 1H, J = 5.5 Hz), 4.41 (s, 1H), 3.29-3.27 (m, 4H), 2.99-2.94 (m, 2H), 2.24-2.22 (m, 4H), 1.93-1.90 (m, 2H), 1.47-1.44 (m, 2H), 1.37-1.33 (m, 2H), 1.21-1.20 (m, 4H); MS (ESI) m / z 475.4 (M ⁺ + H) .

Example 22: Synthesis of compound 1649 Step 1: Synthesis of methyl 7- (4- (hydroxydiphenylmethyl) piperidine-1-carboxamido) heptanoate (Formula 7-4)

To a solution of methyl 7-aminoheptanoate hydrochloride (0.366 g, 1.870 mmol) and triphosgene (0.277 g, 0.935 mmol) in methylene chloride (10 mL) at 0 ° C. was added N, N-diisopropylethylamine. (0.977 mL, 5.610 mmol) was added and stirred for 1 hour. Diphenyl (piperidin-4-yl) methanol (0.500 g, 1.870 mmol) was added to the reaction mixture and stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 50%), the desired compound of formula 7-4 (0.609 g, 71.9%) Obtained as a colorless oil.

Step 2: Synthesis of methyl 7- (4- (fluorodiphenylmethyl) piperidine-1-carboxamide) heptanoate (Formula 7-5)

Diethylaminosulfur trifluoride (DAST, 0.114 mL, 0.862 mmol) was prepared by dissolving the compound of formula 7-4 (0.300 g, 0.663 mmol) prepared in Step 2 in methylene chloride (5 mL) at 0 ° C. ) And stirred at room temperature for 16 hours. Water was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 50%), the desired compound of formula 7-5 (0.143 g, 47.5%) Obtained as a white solid.

Step 3: Synthesis of 4- (fluorodiphenylmethyl) -N- (7- (hydroxyamino) -7-oxoheptyl) piperidine-1-carboxamide (Compound 1649)

  The compound of formula 7-5 prepared in Step 2 (0.140 g, 0.308 mmol) and hydroxylamine (50.00% aqueous solution, 0.188 mL, 3.080 mmol) were dissolved in methanol (3 mL) at 0 ° C. The solution was stirred at room temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, methanol (10 mL) and saturated aqueous sodium hydrogen carbonate solution (90 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with water, and dried. The desired compound 1649 (0.122 g, 87.0%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.49-7.47 (m, 4H), 7.37-7.33 (m, 4H), 7.26-7.22 (m, 2H), 6.36 (t, 1H, J = 5.5 Hz ), 3.95-3.92 (m, 2H), 2.98-2.79 (m, 3H), 2.65-2.59 (m, 2H), 1.93-1.89 (m, 2H), 1.47-1.44 (m, 2H), 1.36-1.33 (m, 2H), 1.29 - 1.20 (m, 8H); MS (ESI) m / z 456.6 (M + + H).

Example 23: Synthesis of compound 1719 Step 1: Synthesis of tert-butyl 4- (phenylamino) piperidine-1-carboxylate (Formula 6-2)

  tert-Butyl 4-oxopiperidine-1-carboxylate (5.000 g, 25.94 mmol), aniline (2.749 mL, 30.113 mmol), and acetic acid (2.155 mL, 37.641 mmol) were added at room temperature to methylene chloride ( 50 mL) was added to a solution of sodium triacetoxyborohydride (5.850 g, 27.604 mmol) and stirred at the same temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (100 mL) was added to the concentrate and stirred, and the precipitated solid was filtered, washed with hexane, and dried to give the desired compound of formula 6-2 (4.640 g, 66.9%) as white. Obtained as a solid.

Step 2: Synthesis of tert-butyl 4-((3-fluorophenyl) (phenyl) amino) piperidine-1-carboxylate (Formula 6-3)

Compound of formula 6-2 prepared in Step 1 (0.500 g, 1.809 mmol), 1-fluoro-3-iodobenzene (0.422 g, 1.900 mmol), palladium acetate (II, 0.016 g, 0 0.072 mmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (0.051 g, 0.081 mmol), and potassium tert-butoxide (0.254 g, 2.261 mmol) at 110 ° C. A solution dissolved in toluene (5 mL) was stirred at the same temperature for 16 hours, and then the temperature was lowered to room temperature to complete the reaction. Saturated aqueous sodium chloride solution was poured into the filtrate from which the reaction mixture was filtered through a celite pad to remove the solid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 10%), the desired compound of formula 6-3 (0.292 g, 43.6%) Obtained as a yellow solid.

Step 3: Synthesis of N- (3-fluorophenyl) -N-phenylpiperidin-4-amine hydrochloride (chemical formula 6-4)

  Hydrogen chloride (4.00 M solution in dioxane, 0.962 mL, 3) was prepared by dissolving the compound of Formula 6-3 prepared in Step 2 (0.285 g, 0.769 mmol) in methylene chloride (10 mL) at room temperature. 846 mmol) and stirred at the same temperature for 16 hours. After the reaction mixture was removed of the solvent under reduced pressure, the resulting material was used as such without further purification (0.212 g, 89.8%, yellow solid).

Step 4: Synthesis of methyl 7- (4-((3-fluorophenyl) (phenyl) amino) piperidine-1-carboxamide) heptanoate (Formula 6-6)

To a solution of methyl 7-aminoheptanoate hydrochloride (0.135 g, 0.691 mmol) and triphosgene (0.103 g, 0.345 mmol) in methylene chloride (10 mL) at 0 ° C. was added N, N-diisopropylethylamine. (0.361 mL, 2.073 mmol) was added and stirred at the same temperature. The compound of Formula 6-4 prepared in Step 3 (0.212 g, 0.691 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 4g cartridge ethyl acetate / hexane = 0% to 50%), the desired compound of formula 6-6 (0.219 g, 69.6%) Obtained as a colorless oil.

Step 5: Synthesis of 4-((3-fluorophenyl) (phenyl) amino) -N- (7- (hydroxyamino) -7-oxoheptyl) piperidine-1-carboxamide (Compound 1719)

  Compound of formula 6-6 prepared in Step 4 (0.219 g, 0.481 mmol), hydroxylamine (50.00% aqueous solution, 0.294 mL, 4.807 mmol), and potassium hydroxide (0.270 g, 4 .807 mmol) in methanol (5 mL) at 0 ° C. was stirred at room temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, methanol (1 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with hexane, dried, The desired compound 1719 (0.196 g, 89.3%) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.44-7.42 (m, 2H), 7.32-7.28 (m, 1H), 7.16-7.10 (m, 1H), 7.05-7.03 (m, 2H), 6.51 -6.46 (m, 1H), 6.37-6.32 (m, 3H), 4.10-4.08 (m, 1H), 3.97-3.94 (m, 2H), 2.92-2.87 (m, 2H), 2.83-2.77 (m, 2H), 1.92-1.88 (m, 2H), 1.85-1.52 (m, 2H), 1.45-1.41 (m, 2H), 1.30-1.27 (m, 2H), 1.16-1.08 (m, 4H), 1.06- 1.00 (m, 2H); MS (ESI) m / z 457.5 (M + + H).

Example 24: Synthesis of compound 1726 Step 1: Synthesis of tert-butyl 4- (phenyl (4- (trifluoromethyl) phenyl) amino) piperidine-1-carboxylate (Formula 6-3)

tert-Butyl 4- (phenylamino) piperidine-1-carboxylate (1.000 g, 3.618 mmol), 1-iodo-4- (trifluoromethyl) benzene (1.033 g, 3.799 mmol), palladium acetate ( II, 0.032 g, 0.145 mmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (0.101 g, 0.163 mmol), and potassium tert-butoxide (0.507 g, 4 .523 mmol) in toluene (5 mL) at 110 ° C. was stirred at the same temperature for 16 hours, and then the temperature was lowered to room temperature to complete the reaction. The reaction mixture was filtered through a celite pad, water was poured into the filtrate from which the solid had been removed, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 10%), the desired compound of formula 6-3 (0.040 g, 2.9%) Obtained as a brown oil.

Step 2: Synthesis of N-phenyl-N- (4- (trifluoromethyl) phenyl) piperidin-4-amine hydrochloride (Formula 6-4)

  Hydrochloric acid (4.00 M solution, 3.118 mL, 12.471 mmol) was added to a solution of the compound of formula 6-3 (0.890 g, 2.494 mmol) prepared in Step 1 in methylene chloride (20 mL) at room temperature. In addition, the mixture was stirred at the same temperature for 16 hours. After removing the solvent under reduced pressure in the reaction mixture, the resulting material was used as such without further purification (0.890 g, 100.0%, yellow solid).

Step 3: Synthesis of methyl 7- (4- (phenyl (4- (trifluoromethyl) phenyl) amino) piperidine-1-carboxamide) heptanoate (Formula 6-6)

To a solution of methyl 7-aminoheptanoate hydrochloride (0.219 g, 1.121 mmol) and triphosgene (0.166 g, 0.561 mmol) in methylene chloride (10 mL) at 0 ° C. was added N, N-diisopropylethylamine. (0.586 mL, 3.363 mmol) was added and stirred at the same temperature. The compound of formula 6-4 prepared in Step 2 (0.400 g, 1.121 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 50%), the desired compound of formula 6-6 (0.277 g, 48.9%) Obtained as a colorless oil.

Step 4: Synthesis of N- (7- (hydroxyamino) -7-oxoheptyl) -4- (phenyl (4- (trifluoromethyl) phenyl) amino) piperidine-1-carboxamide (Compound 1726)

  A solution of the compound of formula 6-6 prepared in Step 3 (0.170 g, 0.336 mmol) and hydroxylamine (50.00% aqueous solution, 0.205 mL, 3.356 mmol) in methanol (5 mL) at room temperature To the mixture was added potassium hydroxide (0.188 g, 3.356 mmol), and the mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with hexane, and dried to give the desired compound 1726 (0.139 g, 81.8%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.21-7.16 (m, 4H), 6.97-6.93 (m, 2H), 6.84-6.80 (m , 1H), 6.67-6.65 (m, 2H), 6.36-6.34 (m, 1H), 4.07-4.02 (m, 1H), 3.98-3.95 (m, 2H), 2.93-2.88 (m, 2H), 2.81 -2.75 (m, 2H), 1.93-1.89 (m, 2H), 1.85-1.82 (m, 2H), 1.45-1.43 (m, 2H), 1.31-1.27 (m, 2H), 1.18-1.15 (m, 4H), 1.05 - 1.01 (m , 2H); MS (ESI) m / z 457.5 (M + + H).

Example 25: Synthesis of compound 1734 Step 1: Synthesis of tert-butyl 4-((4-fluorophenyl) (phenyl) amino) piperidine-1-carboxylate (Formula 6-3)

tert-Butyl 4- (phenylamino) piperidine-1-carboxylate (0.820 g, 2.967 mmol), 1-fluoro-4-iodobenzene (0.358 mL, 3.115 mmol), palladium acetate (II, 0.8). 027 g, 0.119 mmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (0.083 g, 0.134 mmol), and potassium tert-butoxide (0.416 g, 3.709 mmol). A solution dissolved in toluene (5 mL) at 110 ° C. was stirred at the same temperature for 16 hours, and then the temperature was lowered to room temperature to complete the reaction. The reaction mixture was filtered through a celite pad, water was poured into the filtrate from which the solid had been removed, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 12 g cartridge ethyl acetate / hexane = 0% to 10%), the desired compound of formula 6-3 (0.352 g, 32.0%) Obtained as a light yellow solid.

Step 2: Synthesis of N- (4-fluorophenyl) -N-phenylpiperidin-4-amine hydrochloride (Formula 6-4)

  A solution of the compound of Formula 6-3 prepared in Step 1 (0.340 g, 0.918 mmol) and hydrochloric acid (4.00 M solution, 1.147 mL, 4.589 mmol) in methylene chloride (5 mL) at room temperature was prepared. And stirred at the same temperature for 18 hours. After removing the solvent under reduced pressure in the reaction mixture, the resulting material was used as such without further purification (0.281 g, 99.8%, yellow solid).

Step 3: Synthesis of methyl 7- (4-((4-fluorophenyl) (phenyl) amino) piperidine-1-carboxamide) heptanoate (Formula 6-6)

To a solution of methyl 7-aminoheptanoate hydrochloride (0.179 g, 0.913 mmol) and triphosgene (0.135 g, 0.456 mmol) in methylene chloride (10 mL) at 0 ° C. was added N, N-diisopropylethylamine. (0.477 mL, 2.738 mmol) was added and stirred at the same temperature. The compound of Formula 6-4 prepared in Step 2 (0.280 g, 0.913 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 4g cartridge ethyl acetate / hexane = 0% to 50%), the desired compound of formula 6-6 (0.185 g, 44.5%) Obtained as a colorless oil.

Step 4: Synthesis of 4-((4-fluorophenyl) (phenyl) amino) -N- (7- (hydroxyamino) -7-oxoheptyl) piperidine-1-carboxamide (Compound 1734)

  The compound of formula 6-6 prepared in Step 3 (0.260 g, 0.569 mmol) and hydroxylamine (50.00% aqueous solution, 0.348 mL, 5.695 mmol) were dissolved in methanol (5 mL) at 0 ° C. The solution was stirred at room temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with hexane, and dried to give the desired compound 1734 (0.185 g, 71.2%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.21-7.16 (m, 4H), 6.97-6.93 (m, 2H), 6.84-6.80 (m , 1H), 6.67-6.65 (m, 2H), 6.36-6.34 (m, 1H), 4.07-4.02 (m, 1H), 3.98-3.95 (m, 2H), 2.93-2.88 (m, 2H), 2.81 -2.75 (m, 2H), 1.93-1.89 (m, 2H), 1.85-1.82 (m, 2H), 1.45-1.43 (m, 2H), 1.31-1.27 (m, 2H), 1.18-1.15 (m, 4H), 1.05 - 1.01 (m , 2H); MS (ESI) m / z 457.5 (M + + H).

Example 26: Synthesis of compound 1763 Step 1: Synthesis of tert-butyl 7-benzhydryl-2,7-diazaspiro [3.5] nonane-2-carboxylate (Formula 4-5)

  (Chloromethylene) dibenzene (0.439 mL, 2.467 mmol), tert-butyl 2,7-diazaspiro [3.5] nonane-2-carboxylate (0.614 g, 2.714 mmol), and potassium carbonate (1 (.705 g, 12.335 mmol) in N, N-dimethylformamide (10 mL) at 80 ° C. was stirred at the same temperature for 16 hours, and then the temperature was lowered to room temperature to complete the reaction. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was stirred with ethyl acetate (100 mL), the precipitated solid was filtered, washed with ethyl acetate and dried to give the desired compound of formula 4-5 (0.411 g, 42.4%). Obtained as a white solid.

Step 2: Synthesis of 7-benzhydryl-2,7-diazaspiro [3.5] nonane hydrochloride (formula 4-6)

  Hydrochloric acid (4.00M solution in dioxane, 1.309 mL, 5.235 mmol) was prepared by dissolving the compound of Formula 4-5 (0.411 g, 1.047 mmol) prepared in Step 1 in methylene chloride (8 mL) at room temperature. ) And stirred at the same temperature for 16 hours. The reaction mixture was removed under reduced pressure and the resulting material was used as such without further purification (0.344 g, 99.9%, white solid).

Step 3: Synthesis of methyl 6- (7-benzhydryl-2,7-diazaspiro [3.5] nonane-2-carboxamide) hexanoate (Formula 4-7)

To a solution of methyl 6-aminohexanoate hydrochloride (0.100 g, 0.549 mmol) and triphosgene (0.078 g, 0.261 mmol) in methylene chloride (5 mL) at 0 ° C. was added N, N-diisopropylethylamine. (0.273 mL, 1.569 mmol) was added and stirred at the same temperature. The compound of Formula 4-6 prepared in Step 2 (0.172 g, 0.523 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 4g cartridges methanol / methylene chloride = 0% to 3%), the desired compound of formula 4-7 (0.148 g, 61.0%) Obtained as a bright red solid.

Step 4: Synthesis of 7-benzhydryl-N- (6- (hydroxyamino) -6-oxohexyl) -2,7-diazaspiro [3.5] nonane-2-carboxamide (Compound 1763)

  A solution of the compound of formula 4-7 prepared in Step 3 (0.148 g, 0.319 mmol) and hydroxylamine (50.00% aqueous solution, 0.195 mL, 3.192 mmol) in methanol (5 mL) at room temperature Was stirred at the same temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, methanol (1 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with hexane, and dried. The resulting material was recrystallized with ethyl acetate (10 mL) at 25 ° C. and the solid obtained by filtration was washed with hexane and dried to give the desired compound 1863 (0.044 g, 29.7%). Obtained as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.40-7.38 (m, 4H), 7.29-7.25 (m, 4H), 7.18-7.14 (m, 2H), 6.18-6.17 (m, 1H), 4.26 (s, 1H), 3.42-3.33 (m, 4H), 2.91-2.90 (m, 2H), 2.20-2.19 (m, 4H), 1.85-1.82 (m, 2H), 1.65-1.64 (m, 4H) , 1.43-1.40 (m, 2H), 1.33-1.30 (m, 2H), 1.19-1.15 (m, 2H); MS (ESI) m / z 465.3 (M ⁺ + H).

Example 27: Synthesis of compound 1764 Step 1: Synthesis of methyl 7- (7-benzhydryl-2,7-diazaspiro [3.5] nonane-2-carboxamide) heptanoate (Formula 4-7)

To a solution of methyl 7-aminoheptanoate hydrochloride (0.107 g, 0.549 mmol) and triphosgene (0.078 g, 0.261 mmol) in methylene chloride (5 mL) at 0 ° C. was added N, N-diisopropylethylamine. (0.273 mL, 1.569 mmol) was added and stirred at the same temperature. The compound of Formula 4-6 (0.172 g, 0.523 mmol) prepared in Step 2 of Example 26 was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column chromatography; was purified and concentrated (SiO _2, 4g cartridges methanol / methylene chloride = 0% to 3%), the desired compound of formula 4-7 (0.136 g, 54.4%) Obtained as a bright red solid.

Step 2: Synthesis of 7-benzhydryl-N- (7- (hydroxyamino) -7-oxoheptyl) -2,7-diazaspiro [3.5] nonane-2-carboxamide (Compound 1764)

  A solution of the compound of Formula 4-7 prepared in Step 1 (0.136 g, 0.285 mmol) and hydroxylamine (50.00%, 0.188 g, 2.847 mmol) in methanol (5 mL) at room temperature was prepared. And stirred at the same temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, methanol (1 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with hexane, and dried. The resulting material was recrystallized with ethyl acetate (10 mL) at 25 ° C., filtered and the resulting solid was washed with hexane and dried to give compound 1764 (0.021 g, 15.4%) as a white solid. Got as.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.40-7.38 (m, 4H), 7.29-7.25 (m, 4H), 7.18-7.14 (m, 2H), 6.16 (t, 1H, J = 5.5 Hz ), 4.26 (s, 1H), 3.42-3.41 (m, 4H), 2.92-2.88 (m, 2H), 2.19-2.18 (m, 4H), 1.88-1.84 (m, 2H), 1.65-1.64 (m , 4H), 1.43 - 1.42 ( m, 2H), 1.32 - 1.31 (m, 2H), 1.19 - 1.18 (m, 4H); MS (ESI) m / z 479.6 (M + + H).
Protocol for measuring and analyzing the activity of the compounds of the invention
<Experimental Example 1> Confirmation of inhibition of HDAC enzyme activity (in vitro)
Since selective HDAC6 inhibitors are important for the selectivity of HDAC1 inhibition that causes side effects, the selectivity and cell selectivity of HDAC1 / 6 enzyme (HDAC1: Histone acetate / HDAC6: Tubulin acetate) was examined.
1. Experimental Method HDAC1 Fluorometric Drug Discovery Assay Kit (Enzosciences: BML-AK511) and HDAC6 human recombinant (Calbiochem: 382180) were used to measure the ability of the test substance to inhibit HDAC enzyme. In the case of HDAC1 assay, the treatment was performed at a concentration of 100, 1000, and 10000 nM, and in the case of HDAC6 assay, the treatment was performed at a concentration of 0.1, 1, 10, 100, and 1000 nM. After the sample treatment, the mixture was reacted at 37 ° C. for 60 minutes, treated with Developer, reacted at 37 ° C. for 30 minutes, and then fluorescence intensity (Ex 390, Em 460) was measured using FlexStatin3 (Molecular device).

2. Experimental results The results are shown in Table 4.

  As shown in Table 4 above, the control compound ACY-1215 has 48-fold selectivity with 0.01 μM HDAC6 and 0.48 uM HDAC1, and compound 1102 has 0.004 uM HDAC6 and 3 HDAC1. .84 uM with 960-fold selectivity, Compound 1124 with 0.024 uM for HDAC6 and 170-fold selectivity with 4.09 uM for HDAC1, Compound 1209 with 193 for HDAC6 with 0.006 uM and HDAC1 with 1.16 uM The novel derivative of the present invention showed excellent HDAC1 / 6 enzyme selectivity, such as double selectivity.

Experimental Example 2 Efficacy of Compound 1102 in Adjuvant-Induced Arthritis Model Experimental Method 100 ul of Complete Freund's adjuvant (Chondrex) was injected intradermally into the tail of Lewis rats to induce arthritis. From the day before induction, the groups were divided based on body weight, and drugs were orally administered once a day according to their respective concentrations.

  Clinical score and body weight were measured twice a week from the first drug administration day. The clinical score was divided into 0 to 4 points, and the total clinical score was evaluated by evaluating each rat's paw and then adding up (normal: 0, most severe edema: 16).

2. Experimental Results The experimental results are shown in FIG. The efficacy of the arthritis model is evaluated by the degree of serious edema of the joint, and the higher the degree of edema, the higher the score.

  As shown in FIG. 1, in the case of the group not treated with drugs (Vehicle), the severe edema was 9 to 11 points, and the group to which Compound 1102 was administered 1 mg / kg as shown in FIG. Then, 6 to 8 points, the group administered with 10 mg / kg was 4 to 6 points, and the group administered with 50 mg / kg was 1 to 3 points, indicating that the symptoms of arthritis were improved.

Claims (9)

A compound represented by the following chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
In the chemical formula I, X is
A heterocyclic alkyl selected from the group consisting of;
(Where Z and W are each independently C or N, and at least one of Z and W is N;
a, b, c, and d are each independently 1, 2 or 3,
R ₃ , R ₄ , R ₅ , and R ₆ are each independently —H or —C ₁ -C ₄ alkyl)
Y is C or N;
A and B are each independently, -C ₁ -C ₄ alkyl, -C ₆ -C ₁₀ aryl, -C ₃ -C ₁₂ heteroaryl, -C ₃ -C ₁₀ cycloalkyl, -C ₂ -C ₁₀ Heterocycloalkyl, or —C ₃ -C ₁₀ cycloalkenyl, wherein one or more hydrogens of —C ₁ -C ₄ alkyl may be substituted with —OH or halogen, —C ₆ — or C ₁₀ aryl, -C ₃ -C ₁₂ heteroaryl, -C ₃ -C ₁₀ cycloalkyl, -C ₂ -C ₁₀ heterocycloalkyl, and -C ₃ -C ₁₀ cycloalkenyl is unsubstituted respectively, Or one or more hydrogens may be optionally substituted with —OH, —C ₁ -C ₄ alkyl, —OC ₁ -C ₄ alkyl, —CF ₃ , or halogen);
Q is C═O or SO ₂ ;
R ₁ is —H or —C ₁ -C ₄ alkyl;
R2 _{is, -H, -OH, -C 1 -C} 4 alkyl, -C ₁ -C ₄ alkyl hydroxy, halogen, or anything in no (null) (wherein, when Y is C, R ₂ is - H, —OH, —C ₁ -C ₄ alkyl, or —C ₁ -C ₄ alkyl hydroxy, and when Y is N, R ₂ is nothing); and n is 1, 2, 3 or 4. X is
Is;
(Where Z and W are each independently C or N, and at least one of Z and W is N;
a, b, c, and d are each independently 1, 2, or 3;
R ₃ , R ₄ , R ₅ , and R ₆ are each independently —H or —C ₁ -C ₄ alkyl)
Y is C or N;
A and B are each independently —C ₁ -C ₄ alkyl, —C ₆ -C ₁₀ aryl, or —C ₃ -C ₁₂ heteroaryl (wherein one of —C ₁ -C ₄ alkyl). One or more hydrogens may be substituted with —OH or halogen, and —C ₆ -C ₁₀ aryl or —C ₃ -C ₁₂ heteroaryl are each unsubstituted or substituted with one or more hydrogens. Optionally substituted with —OH, —C ₁ -C ₄ alkyl, —OC ₁ -C ₄ alkyl, —CF ₃ , or halogen);
Q is C═O or SO ₂ ;
R ₁ is —H or —C ₁ -C ₄ alkyl;
R ₂ is —H, —OH, halogen, or null (where Y is C, R ₂ is —H, —OH, or halogen, and Y is N) R ₂ is nothing); and n is 1, 2, 3, or 4; a compound of formula I according to claim 1, its optical isomer, Or a pharmaceutically acceptable salt thereof. X is
Is;
(Where Z and W are each independently C or N, and at least one of Z and W is N;
R ₃ and R ₄ are each independently —H or —C ₁ -C ₄ alkyl)
Y is C or N;
A and B are each independently —C ₁ -C ₄ alkyl, —C ₆ -C ₁₀ aryl, or —C ₃ -C ₁₂ heteroaryl (wherein one of —C ₁ -C ₄ alkyl). One or more hydrogens may be substituted with —OH or halogen, and —C ₆ -C ₁₀ aryl or —C ₃ -C ₁₂ heteroaryl are each unsubstituted or substituted with one or more hydrogens. Optionally substituted with —OH, —C ₁ -C ₄ alkyl, —OC ₁ -C ₄ alkyl, —CF ₃ , or halogen);
Q is C = O;
R ₁ is —H or —C ₁ -C ₄ alkyl;
R2 is, -H, -OH, halogen, or anything in no (null) (wherein, when Y is C, R ₂ is, -H, -OH, or halogen, when Y is N, R ₂ is nothing); and n is 3.
The compound represented by the chemical formula I according to claim 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The compound represented by the chemical formula I is a compound described in the following table, the compound represented by the chemical formula I according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Possible salt:
The compound represented by the chemical formula I is a compound shown in the following table, the compound represented by the chemical formula I according to claim 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Possible salt:
  A histone deacetylase-mediated compound comprising as an active ingredient the compound represented by the formula I according to any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating a disease.   The histone deacetylase-mediated disease is a cell proliferative disease, inflammatory disease, autosomal dominant genetic disease, metabolic disease due to genetic factors, autoimmune disease, acute chronic neurological disease, hypertrophy, heart failure, eye disease, or neurodegeneration The pharmaceutical composition according to claim 6, which is a disease.   Administration of a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. A method for treating histone deacetylase-mediated diseases.   The compound represented by the formula I according to any one of claims 1 to 5, an optical isomer thereof, or a pharmacologically thereof in the manufacture of a medicament for the treatment of a histone deacetylase-mediated disease. Use of acceptable salt.